Substituted Oxoisoindoline Compounds for Cancer Treatment

Abstract

Formula (I): [0003] Disclosed is a compound of formula TIFF2023520759000153.tif32147, or a salt thereof, wherein ring A is a carbon-bonded ring; and ring A, R, and n are defined in this disclosure. Also disclosed is a method of using the compound and a pharmaceutical composition containing the compound to inhibit Helios protein. These compounds are useful for treating viral infections and proliferative diseases (e.g., cancer).

Description

Technical Field

[0001] (Related Application) This application claims the benefit of U.S. Provisional Application No. 62 / 993,144, filed Mar. 23, 2020, the entire contents of which are incorporated herein by reference.

[0002] (Description) The present invention generally relates to substituted oxoisoindoline compounds that inhibit Helios protein. The present invention provides substituted oxoisoindoline compounds, compositions containing such compounds, and methods of using them. Further, the present invention relates to pharmaceutical compositions containing at least one compound described herein that are effective for the treatment of proliferative diseases (such as cancer) and viral infections.

Background Art

[0003] Regulatory T cells (Tregs) play an essential role in maintaining self-tolerance and immune homeostasis by suppressing intense immune responses and inflammatory reactions and maintaining immune unresponsiveness. By maintaining a phenotype that exhibits a stable immunosuppressive effect, Tregs suppress excessive immune responses and prevent or alleviate autoimmune diseases. The presence of Tregs in human tumor tissues has been reported in numerous studies. Studies have shown a clear negative correlation between the number of Tregs and the infiltration and survival rate of T cells into tumors (Curiel et al., 2004, Nat. Med. 10: 942-949; Viguier et al., 2004, J Immuno. 1173:1444-1453; Beyer et al., 2006, Blood 108: 804-811; Zou et al., 2006, Nat. Rev. Immunol. 6: 295-307), implicitly suggesting that Tregs potentially play an important role in inhibiting effective anti-tumor immune construction. Previous evidence has shown that in rodents and humans, Foxp3+CD25+CD4+ Tregs preferentially infiltrate tumors and seemingly inhibit the immune response against tumor cells. Once activated by a specific antigen, Tregs behave antigen-nonspecifically in vitro and suppress killer T cells by overlooking them (Takahashi et al., 1998, Int Immunol. 10:1969-80; Thornton et al., 1998, J Exp. Med. 188:287-96). Foxp3+CD25+CD4+ Tregs can seemingly suppress a wide range of anti-tumor immune responses, including CD4+ helper T cells, CD8+ T cells, natural killer cells, and natural killer T cells (Tanaka et al., 2017, Cell Research 27:109-118). When the CD25+CD4+ Tregs in tumors decrease, the cytokine environment in the tumor part changes, and established tumors regress (Yu et al., 2005, J Exp Med. 201: 779-91).Furthermore, transplantation of CD4+ T cells lacking Tregs significantly increases the anti-tumor immune response compared to transplantation of Tregs containing T cells (Antony et al., 2005, J Immunol 174:2591-601). Tumor-infiltrating Tregs activated by either tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific anti-tumor immune responses. Modulating the activity of key factors that control Treg differentiation means that it is a promising strategy for treating certain diseases such as cancer and viral infections.

[0004] FoxP3+ CD4 Tregs are highly stable. Studies to understand this genetic mechanism are still being conducted to confirm whether their phenotype remains stable even after the expansion of inflammation, infection, or autoimmune diseases. Transcription factors (TFs) involved in maintaining the stable immunosuppressive phenotype of Tregs can be used in this study. The Helios (IKZF2) gene, a member of the Ikaros family of TFs, is different from other Ikaros family members based on its selective expression in thymocytes undergoing negative selection, as well as in CD4 and CD8 T cells of the inhibitory differentiation lineage. Helios is expressed by two regulatory T cell lineages, FoxP3+ CD4+ and Ly49+ CD8+ Tregs, which are lineages essential for maintaining self-tolerance (Kim et al., 2015, Science 350:334-339; Sebastian et al., 2016, J Immunol 196:144-155). Interestingly, recent studies have suggested that Helios is not required for the activity of Tregs in the steady state but is essential for controlling the gene program of FoxP3+ CD4 Tregs during inflammation to maintain a stable phenotype and enhance inhibitory function (Thornton et al., 2010, J Immunol. 184:3433-3441; Kim et al., 2015). The expression of Helios has been shown to be very important for Tregs to maintain an immunosuppressive and immunologically unresponsive phenotype against strong inflammatory responses. Activating the IL-2Rα-STAT5 pathway has been shown to be an important relevant factor for Tregs to survive and ensure their stability (Kim et al., 2015). Helios plays an essential role in maintaining the phenotype of FoxP3+ CD4 Tregs to prevent autoimmune diseases in the presence of highly activated autoreactive T cells obtained from Scurfy mice lacking the forkhead domain of FoxP3 by exerting a major lymphocyte-intrinsic inhibitory activity. Bone marrow chimeras reconstituted with Helios- / - / Scurfy bone marrow (BM) (Helios+ excepted) / + / Scurfy BM cells developed autoimmunity rapidly (Kim et al., 2015).These results indicated that Helios is important for the selection, differentiation, and functional expression of autoreactive T cells. Immunosuppression by Tregs can impede the anti-tumor immune response. Selective deficiency of Helios in FoxP3+ CD4 Tregs renders Tregs unstable, and intratumoral CD4 Tregs change into effector T cells (Teffs). When intratumoral Tregs become unstable, Tregs are converted, and as a result of the reduced suppressive action of Tregs, the number of Teff cells in the tumor can increase. Furthermore, poor IL-2 responsiveness was observed in intratumoral Tregs lacking Helios. This results in a decrease in the number of activated Tregs and can contribute to an increase in intratumoral Teff activity. Interactions between tumor cells and infiltrating immune cells promote the secretion of inflammatory mediators (such as TNF-α, IL-6, IL-17, IL-1, and TGF-β), forming a local inflammatory environment (Kim et al., 2015).

[0005] Lineage instability of Helios-deficient Tregs is also caused by reduced FoxP3 expression, resulting in the production of inflammatory cytokines and effector T cells. The transformation of Helios-deficient Tregs into effector cells within the tumor tissue microenvironment is associated with increased expression of genes governing the Teff phenotype (Yates et al., 2018, PNAS, 2018, 115: 2162-2167). Helios deficiency results in an unstable phenotype only within the tumor microenvironment (TME), but not in peripheral lymphoid organs (Nakagawa et al., 2016, PNAS 113: 6248-6253). In chronically inflamed TME, Helios deficiency in Tregs increases helper T cells for TFs and effector cytokines, and can significantly alleviate the suppressive gene program for helper T cell differentiation. A subpopulation of Tregs with high affinity for self-antigens showed increased GITR / PD-1 expression and increased responsiveness to self-antigens, which are evident in the genetic alterations of these Helios-deficient Tregs, which combined promote the conversion of Tregs to Teffs in the TME and increase T cell receptor (TCR) engagement and co-stimulatory receptor expression by Tregs, suggesting that the gene expression alterations that are a key feature of Treg conversion vary depending on the immune environment (Yates et al., 2018).

[0006] Reduced Helios expression in FoxP3+CD4 Tregs can convert memory Tregs into Teff cells expressing tumor antigen-specific autoreactive T cell receptors. In chronic inflammatory conditions due to tumor growth, the altered Treg properties can be selectively induced. Helios-deficient Tregs express TCRs with a high affinity for self-peptide / MHC, which can promote stable activation of Tregs in the TME (Yates et al., 2018). Since the autoreactivity of TCRs in CD4 Tregs is increased compared to conventional T cells, the change in Tregs can produce extremely potent effector CD4 T cells along with suppressing the inhibitory effect mediated by Tregs in the TME. Also, a method that selectively converts intratumoral Tregs into Teff cells without affecting the systemic Treg population would be a more effective strategy. As a key factor for maintaining the amount of Tregs and the functional stability in response to various immune responses, Helios can be pharmacologically relevant to strategies for enhancing current cancer immunotherapy. Since the change from Tregs to Teffs can be limited to the inflammatory tumor microenvironment, antibodies or small molecule-based drugs targeting Helios can lead to an improvement in the immunotherapy of Treg-dependent cancers. Importantly, the change in Helios-deficient Tregs occurs only within the local inflammatory environment of the tumor. This method may not cause autoimmune side effects associated with a decrease in systemic Tregs. Therefore, a strategy that specifically suppresses the Helios-dependent control of intratumoral Tregs is a significant support for improving cancer immunotherapy. Furthermore, it has also been reported that the removal of Foxp3+Tregs enhances the anti-tumor T cell response induced by vaccines (Nishikawa et al., 2010, Int. J. Cancer 127: 759-767). This suggests that a decrease in Helios levels can be effective in enhancing the efficacy of cancer vaccines.

[0007] Antitumor immunotherapy during viral infection may limit the immune response of Treg cells caused by excessive inflammation and inhibit an effective antiviral T cell response, promoting the survival of the virus (Schmitz et al., 2013, PLOS Pathogens 9: e1003362). As a result of chronic infection of mice with lymphocytic choriomeningitis virus, Foxp3+ Tregs significantly proliferated. This implicitly means that there is a potential mechanism by which specific infectious agents can evade the host immune response through the activation and proliferation of Tregs (Punkosdy et al., 2011, PNAS 108: 3677-3682). During the development of chronic virus-related diseases, therapeutic effects can be obtained by reducing the Helios level of activated Tregs.

[0008] Compounds useful as inhibitors of the Helios protein are needed.

[0009] (Summary of the Invention) The present invention provides a substituted oxoisoindoline compound of formula (I) or a salt thereof useful for reducing the Helios protein level and Helios activity level in cells and / or suppressing the Helios expression level.

[0010] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0011] The present invention also provides a method for treating a disease or disorder by reducing the activity of the Helios protein, the method comprising administering to a patient a compound of formula (I) and / or a pharmaceutically acceptable salt thereof.

[0012] The present invention also provides methods and intermediates for use in the manufacture of a compound of formula (I) and / or a salt thereof.

[0013] The present invention also provides a compound of formula (I) and / or a pharmaceutically acceptable salt thereof for use in therapy.

[0014] The present invention also provides the use of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of certain diseases (such as cancer and viral infections), which reduces the Helios protein level and Helios activity level in cells and / or suppresses the Helios expression level in order to control the differentiation of Tregs.

[0015] The compounds of formula (I) and the compositions containing the compounds of formula (I) may be used for the treatment, prevention or prophylaxis of viral infections and various proliferative diseases (such as cancer). The pharmaceutical compositions containing these compounds are useful for the treatment, prevention or suppression of the progression of diseases or disorders (such as viral infections and cancer) at various treatment sites.

[0016] The above and other features of the present invention will be described in a broader scope along with the disclosure.

Mode for Carrying Out the Invention

[0017] The applicant has discovered substituted oxoisoindoline compounds that inhibit the Helios protein by promoting the interaction of the Helios protein with its corresponding E3 ubiquitin ligase complex (Cullin4-Cereblon, CUL4-CRBN). These compounds reduce the Helios protein level and Helios activity level in cells and / or suppress the Helios expression level in order to control the differentiation of Tregs. These compounds are useful for the treatment of certain diseases (such as cancer and viral infections). These compounds provide useful medicaments having desirable stability, bioavailability, therapeutic index, and toxicity values important for their drugability.

[0018] The first aspect of the present invention is at least one formula (I):

Chemical formula

[0019] In certain embodiments, in the formula, each R1 is independently F, Cl, Br, -CN, -OH, -NO2, C 1a alkyl substituted with 0 to 6 R 1-5 alkoxy substituted with 0 to 5 R 1a -CR 1-2 R x R x OCH2(phenyl), -NR y R y -NR x C(O)CH3, -NR x C(O)NR x R x -C(O)H, -C(O)OH, -C(O)O(C 1-2 alkyl), -C(O)NR x R x -C(O)NR x (cyclopropyl), -OC(O)(C 1-2 alkyl), -SO2(C 1-2 alkyl), -NHN(CH3)2, -CH2CH2Si(CH3)3, or is a cyclic group selected from C 3-6 cycloalkyl, phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, and dioxidesthiomorpholinyl, said cyclic group being substituted with 0 to 3 R 1b to provide a compound of formula (I) or a salt thereof.

[0020] One embodiment is a compound of formula (I) or a salt thereof, wherein each R1 is independently F, Cl, Br, -CN, -OH, -NO2, C alkyl substituted with 0 to 6 R 1a alkyl, C alkoxy substituted with 0 to 5 R 1-5 alkyl, -CR 1a alkyl, -CR 1-2 alkoxy, -CR x R x OCH2(phenyl), -NR y R y R, -NR x C(O)CH3, -NR x C(O)NR x R x R, -C(O)H, -C(O)OH, -C(O)O(C 1-2 alkyl), -C(O)NR x R x R, -C(O)NR x (cyclopropyl), -OC(O)(C 1-2 alkyl), -SO2(C 1-2 alkyl), -NHN(CH3)2, -CH2CH2Si(CH3)3, or is a cyclic group selected from C cycloalkyl, phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, and dioxydothiomorpholinyl, and the cyclic group is substituted with 0 to 3 R 3-6 ; each R 1b is independently F, Cl, C alkyl, -CH2F, -CHF2, -CF3, C alkoxy, -OCF3, -C(O)(C 1b alkyl), or -SO2(C 1-2 alkyl); and n is 0, 1, 2, or 3. 1-2 1-2 1-2

[0021]

[0021] One embodiment provides a compound of formula (I) or a salt thereof, wherein each R1 is independently F, Cl, Br, -CN, -OH, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2Cl, -CH2CN, -CH2(phenyl), -CH2OH, -CH2OCH2(phenyl), -OCH3, -OCH2CH3, -OCH2(phenyl), -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH(CH3)CH2CH3), -N(CH3)2, -N(CH2CH3)2, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)H, -C(O)OCH3, -C(O)NH(cyclopropyl), -C(O)NH2, -C(O)N(CH3)2, -CH2CH2Si(CH3)3, -OC(O)CH3, -NHN(CH3)2, cyclopropyl, phenyl, pyridinyl, (benzyl)morpholinyl, (methylsulfonyl)piperazinyl, or acetylpiperazinyl; and n is 0, 1, 2, or 3.

[0022] One embodiment provides a compound of formula (I) or a salt thereof, wherein each R1 is independently F, Cl, Br, -CN, -OH, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2Cl, -CH2CN, -CH2(phenyl), -CH2OH, -CH2OCH2(phenyl), -OCH3, -OCH2CH3, -OCH2(phenyl), -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH(CH3)CH2CH3), -N(CH3)2, -N(CH2CH3)2, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)H, -C(O)OCH3, -C(O)NH(cyclopropyl), -C(O)NH2, -C(O)N(CH3)2, -CH2CH2Si(CH3)3, -OC(O)CH3, -NHN(CH3)2, cyclopropyl, phenyl, pyridinyl, or acetylpiperazinyl; and n is 0, 1, 2, or 3.

[0023] One embodiment is a formula wherein ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof.

[0024] In certain embodiments, ring A is

Chemical formula

[0025] In certain embodiments, ring A is

Chemical formula

[0026] In certain embodiments, ring A is

Chemical formula

[0027] In certain embodiments, ring A is

Chemical formula

[0028] In certain embodiments, ring A is

Chemical formula

[0029] In certain embodiments, ring A is

Chemical formula

[0030] In certain embodiments, ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof, which is as follows.

[0031] In certain embodiments, ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof, which is as follows.

[0032] In certain embodiments, ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof, which is as follows.

[0033] In certain embodiments, ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof, which is as follows.

[0034] In certain embodiments, ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof, which is as follows.

[0035] In certain embodiments, ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof, which is as follows.

[0036] In certain embodiments, ring A is [Chemical formula] To provide a compound of formula (I) or a salt thereof, which is as follows.

[0037] In one embodiment, in the formula, each R1 is independently F, Cl, Br, -CN, -OH, -NO2, C 1a substituted with 0 to 6 R 1-6 alkyl, C 1a substituted with 0 to 6 R 1-3 alkoxy, -CR x R x OCR x R x (phenyl), -NR y R y , -NR x C(O)H, -NR x C(O)(C 1-2 alkyl), -NR x C(O)NR x R x , -C(O)H, -C(O)OH, -C(O)O(C 1-3 alkyl), -C(O)NR x R x , -C(O)NR x (C 3-6 cycloalkyl), -OC(O)(C 1-3 alkyl), -SO2(C 1-3 alkyl), or -NHN(C 1-2 alkyl)2, and provides a compound of formula (I) or a salt thereof. In this embodiment, each R1 is independently F, Cl, Br, -CN, -OH, -NO2, C 1a substituted with 0 to 6 R 1-5 alkyl, C 1a substituted with 0 to 5 R 1-2 alkoxy, -CR x R x OCH2(phenyl), -NR y R y , -NR x C(O)CH3, -NR x C(O)NR x R x , -C(O)H, -C(O)OH, -C(O)O(C 1-2 alkyl), -C(O)NR x R x , -C(O)NR x (cyclopropyl), -OC(O)(C 1-2 alkyl), -SO2(C1-2 Compounds containing an alkyl group or -NHN(CH3)2 are included. In this embodiment, each R1 is independently F, Cl, Br, -CN, -OH, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -CH2C(CH3)3, -CF3, -CH2Cl, -CH2CN, -CH2(phenyl), -CH2OH, -CH2OCH2(phenyl), -OCH3, -OCH2CH3, -OCH2(phenyl), -NH2, -NH(CH3), -NH(CH2CH3), -NH(CH(CH3)CH2CH3), -N(CH3)2, -N(CH2CH3)2, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)H, -C(O)OCH3, -C(O)NH(cyclopropyl), -C(O)NH2, -C(O)N(CH3)2, -OC(O)CH3, or -NHN(CH3)2. Compounds are included.

[0038] One embodiment is a compound of formula (I) or a salt thereof, wherein each R1 is independently C 3-6 A cyclic group selected from cycloalkyl, phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, and dithiomorpholinyl dioxide, said cyclic group being substituted with 0 to 4 R 1b A compound of formula (I) or a salt thereof is provided. In this embodiment, each R1 is independently C 3-6 A cyclic group selected from cycloalkyl, phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, and dithiomorpholinyl dioxide, said cyclic group being substituted with 0 to 3 R 1b Compounds are included. In this embodiment, compounds are also included wherein each R1 is independently cyclopropyl, phenyl, pyridinyl, or acetylpiperazinyl.

[0039] One embodiment provides a compound of formula (I) or a salt thereof, wherein n is 0, 1, 2, or 3. This embodiment includes compounds wherein n is 0, 1, or 2. Further, this embodiment includes compounds wherein n is 1 or 2.

[0040] One embodiment is where ring A is

Chemical formula

[0041] One embodiment is where ring A is

Chemical formula

[0042] One embodiment is where ring A is

Chemical formula

[0043] One embodiment is where ring A is

Chemical formula

[0044] In certain embodiments, in the formula, ring A is

Chemical formula

[0045] In certain embodiments, in the formula, ring A is

Chemical formula

[0046] In certain embodiments, in the formula, ring A is

Chemical formula

[0047] In one embodiment, the compound is 3-[1-oxo-5-(quinolin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (1); 3-[5-(4-aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (2); 3-(5-{8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]Trideca-1(9),2,4,6,10,12-hexen-6-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione(3); 3-[5-(1-Aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione(4); 3-[5-(3-Aminoquinoxalin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione(5); 3-(1-Oxo-5-{7H-pyrrolo[2,3-c]pyridazin-3-yl}-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione(6); 3-[1-Oxo-5-(quinoxalin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione(7); 3-[5-(4-Aminoquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione(8); 3-[1-Oxo-5-(quinazolin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione(9); 3-(5-{2-[(Butan-2-yl)amino]-[1,3]thiazolo[5,4-b]pyridin-5-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione(10); 3-(5-{7-Fluoro-1H-pyrrolo[3,2-c]pyridin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione(11); 3-[5-(4-Methoxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione(12); 3-[1-Oxo-5-(4-Phenylquinolin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione(13); N-Cyclopropyl-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinoline-4-carboxamide(14);3-{5-[6-chloro-4-(diethylamino)quinazolin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (15); 3-[5-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (16); 3-[5-(6-methoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (17); 3-[5-(6-chloroquinoxalin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (18); 3-[5-(7-fluoroisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (19); 3-[5-(5-fluoroisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (20); 3-[5-(1,5-naphthyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (21); 3-[5-(4-aminoquinazolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (22); 3-[5-(6-methylisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (23); 3-[5-(4-methylquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (24); 3-[5-(3-aminoisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (25); 3-[5-(6-fluoroquinoxalin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (26); 3-[5-(6-chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (27);3-[5-(7-chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (28); 3-[5-(6-methoxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (29); ethyl 3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinoxaline-2-carboxylate (30); methyl 2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinoline-6-carboxylate (31); 3-[5-(3-methylquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (32); 3-[5-(8-methoxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (33); 3-[5-(8-chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (34); 3-[5-(6-fluorobenzoxazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (35); 3-[5-(3-chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (36); 3-[5-(4-hydroxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (37); 3-[5-(6-fluorquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (38); 3-[5-(6-methylquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (39); 3-[5-(6-hydroxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (40);Methyl 2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinazoline-7-carboxylate (41); 3-(5-{5-amino-3-[2-(trimethylsilyl)ethyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (42); 3-[5-(2-amino-9H-purin-6-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (43); 3-[5-(6-amino-7H-purin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (44); 3-(5-{6-amino-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (45); 3-{5-[5-amino-1-(2,2-dimethylpropyl)-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (46); 3-[5-(5-amino-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (47); N-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}acetamide (48); 3-{5-[1-(dimethylamino)isoquinolin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (49); 3-{5-[1-(methylamino)isoquinolin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (50); 3-{5-[5-(methylamino)-1,6-naphthyridin-7-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (51);N-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}-N-methylacetamide (52); 3-[5-(6-amino-1,7-naphthyridin-8-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (53); 3-[5-(3-amino-5-methoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (54); 3-(5-(4-(4-acetylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55); 3-(5-{4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (56); 3-[5-(5-amino-1,6-naphthyridin-7-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (57); 3-[5-(3,6-dimethoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (58); 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinoline-3-carbonitrile (59); 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]thieno[3,2-c]pyridine-2-carbaldehyde (60); 3-{5-[1-methyl-4-(methylamino)-1H-imidazo[4,5-c]pyridin-6-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (61); 3-(5-{2-methyl-4-oxo-4H-pyrano[2,3-b]pyridin-7-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (62);3-{5-[5,7-Dichloro-3-(dimethylamino)isoquinolin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (63); 3-[5-(1,7-Naphthyridin-8-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (64); 3-(5-{2-Aminoimidazo[1,2-b]pyridazin-6-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (65); 3-[5-(Isoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (66); 3-[5-(Isoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (67); 3-(5-(2-Amino-6-methoxypyrimidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (68); 3-(5-(6-Aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (69); 3-(5-(2-Aminopyrimidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70); 3-(1-Oxo-5-(4-phenylpyrimidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (71); 3-(1-Oxo-5-(4-(pyridin-3-yl)pyrimidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (72); 3-(5-(4-Amino-6-phenyl-1,3,5-triazin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (73); 3-(1-Oxo-5-(4-phenylpyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (74); 3-(1-Oxo-5-(4-(pyridin-2-yl)pyrimidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (75); 3-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridazine-4-carbonitrile (76);6-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridazine-3-carbonitrile (77); 6-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridazine-3-carboxamide (78); 3-[5-(6-Amino-3-nitropyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (79); 4-Amino-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyrimidine-5-carbonitrile (80); 4-Amino-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyrimidine-5-carboxamide (81); (3S)-3-[5-(1-Aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (82); (3R)-3-[5-(1-Aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (83); (3S)-3-[5-(1-Amino-4-ethoxyisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (84); 3-(5-(4-Ethoxyisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (85); 3-(5-(1-Chloro-4-ethoxyisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86); 3-(5-(2,3-Dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87); 3-(5-(1-Methylisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (88); 3-(5-(1-Cyclopropylisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (89);1-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl); Isoquinoline-4-carbonitrile (90); 3-(1-oxo-5-(quinazolin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (91); 3-(5-(6-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (92); 3-(5-(3-chloroquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (93); 3-(5-(3-methoxyquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (94); 3-(5-(3-(ethylamino)quinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95); 3-(5-(3-hydroxyquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (96); 3-(5-(3-cyclopropylquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (97); 3-(5-(3-isopropylquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (98); 3-(1-oxo-5-(3-phenylquinoxalin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (99); 3-(5-(1,6-naphthyridin-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100); 3-(5-(6-amino-3-bromopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (101); 3-(5-(6-aminoisquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (102); 3-(5-(4-methoxyisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (103); 3-(5-(3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (104); 3-(5-(4-(benzyloxy)isoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (105);3-(5-(6-Amino-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (106); 3-(5-(3-(Hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (107); 3-(5-(4-(Hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (108); 3-(1-Oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (109); 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isonicotinonitrile (110); 2-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)acetonitrile (111); 3-(5-(6-Amino-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (112); 3-(5-(2,3-Dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (113); 3-(1-Oxo-5-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-2-yl)piperidine-2,6-dione (114); 3-(1-Oxo-5-(5,6,7,8-tetrahydroisoquinolin-3-yl)isoindolin-2-yl)piperidine-2,6-dione (115); 3-(5-(6-Amino-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (116); 3-(5-(5,6-Diaminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (117); 3-(1-Oxo-5-(1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)isoindolin-2-yl)piperidine-2,6-dione (118); 3-(5-(5-Amino-4,6-dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (119);3-(5-(6-Amino-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120); 3-(5-(4,5-Dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (121); (3S)-3-[5-(1,8-Naphthyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (122); (S)-3-(5-(3-Aminoisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (123); (S)-N-(1-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isoquinolin-3-yl)acetamide (124); 3-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}isoquinoline-1-carbonitrile (125); 3-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}isoquinoline-1-carboxamide (126); (4S)-7-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-2H,3H,4H-pyrano[2,3-b]pyridin-4-yl acetate (127); (4R)-7-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-2H,3H,4H-pyrano[2,3-b]pyridin-4-yl acetate (128); 3-{5-[7-Chloro-4-(dimethylamino)isoquinolin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (129); 1-Amino-3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N,N-dimethylisoquinoline-4-carboxamide (130);3-[5-(1-Amino-4-methylisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (131); 3-[5-(6-Amino-3-cyclopropylpyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (132); 3-[5-(6-Aminoisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (133); N-{1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-6-yl}acetamide (134); 3-{5-[6-Amino-4-(chloromethyl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (135); 3-(1-Oxo-5-{5H,6H,7H,8H,9H-pyrido[2,3-b]azepin-2-yl}-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (136); 3-[1-Oxo-5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (137); 3-{5-[6-(2,2-Dimethylhydrazin-1-yl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (138); 3-(5-(1H-Imidazo[4,5-b]pyridin-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (139); 3-(5-(6-Amino-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140); 3-(5-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (141); 3-(5-(6-Aminopyrazin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (142);3-(5-(2-Amino-6-methylpyrimidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (143); 3-(5-(4,6-Dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (144); 3-(5-(5-Chloro-3-hydroxyisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (145); 3-(5-(6-Methoxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (146); 3-(5-(6-Hydroxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (148); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isonicotinonitrile (149); 3-(5-(1-Amino-5,6,7,8-tetrahydroisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150); 3-(5-(6-Amino-4,5-dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (151); 6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (152); 3-(5-(6-Amino-5-methoxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (153); 3-(5-(6-Amino-5-methoxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (154); 3-[5-(6-Methoxypyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (155); 3-[5-(1-Methoxyisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (156);3-[1-Oxo-5-(1-oxo-1,2-dihydroisoquinolin-3-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (157); 3-(5-{1-Benzyl-1H-pyrrolo[3,2-c]pyridin-6-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (158); 3-(1-Oxo-5-(1H-pyrrolo[3,2-c]pyridin-6-yl)isoindolin-2-yl)piperidine-2,6-dione (159); 3-(1-Oxo-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (160); 3-(5-(1-Benzyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (161); 6-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolino-nitrile (162); 3-(5-(6-Amino-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (163); 3-(5-(6-Amino-4-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (164); 3-(5-(6-Amino-4-chloropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (165); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (166); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridine-3,5-dicarbonitrile (168); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoronicotinonitrile (169); 3-(5-(6-Amino-4-phenylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (170);6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile (171); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-propylnicotinonitrile (172); 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-propylnicotinonitrile (173); 6-Amino-4-(difluoromethyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (174); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-(trifluoromethyl)nicotinonitrile (175); 2-Amino-4-(difluoromethyl)-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (176); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile (177); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile (178); 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile (179); 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methylnicotinonitrile (180); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methoxynicotinonitrile (181); 6-Amino-5-cyclopropyl-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (182); 2-Amino-5-cyclopropyl-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (183);3-(5-(6-Amino-4-(4-benzylpiperazin-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (184); 3-(5-(6-Amino-4-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (185); 3-(5-(4-(4-Acetylpiperazin-1-yl)-6-aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (186); 3-(5-(4-Methyl-6-(methylamino)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (187); 3-(5-(6-(Ethylamino)-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (188); or 3-(5-(4,5-Dimethyl-6-(methylamino)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (189), a compound of formula (I) or a salt thereof is provided.

[0048] The present invention may be implemented in other specific forms without departing from its essence or essential characteristics. The present invention encompasses any combination of the aspects and / or embodiments of the present invention described herein. It is understood that any and all embodiments of the present invention may be combined with any other embodiment for the purpose of explaining further embodiments. It is also understood that the individual elements of the embodiments are meant to be combined with any and all other elements from any embodiment for the purpose of explaining further embodiments.

[0049] The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. For clarity, it is understood that certain features of the invention described in the context of separate embodiments may be combined to form one embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may be combined to form sub-combinations thereof. The embodiments illustrated or specified as preferred herein are intended as examples and not for purposes of limitation.

[0050] Unless otherwise specified herein, terms expressed in the singular may also include the plural. For example, "a" and "an" may refer to either "one" or "one or more".

[0051] The phrase "compound and / or its salt" as used herein refers to at least one compound, at least one salt of a compound, or a combination thereof. For example, a compound of formula (I) and / or its salt includes one compound of formula (I); two compounds of formula (I); a salt of one compound of formula (I); one compound of formula (I) and one or more salts of a compound of formula (I); and salts of two or more compounds of formula (I).

[0052] Unless otherwise specified, any atom with an unsatisfied valence is considered to include sufficient hydrogen atoms to satisfy the valence.

[0053] The definitions described herein prevail over the definitions described in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0054] Definitions of various terms used to describe the present invention are listed below. These definitions apply to the terms used throughout the specification, individually (unless otherwise limited in a particular case) or as part of a larger group.

[0055] Throughout this specification, the groups and substituents may be selected by one of ordinary skill in the art to provide stable moieties and compounds.

[0056] In accordance with the convention used in the art,

Chem.

[0057] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0058] The term "cyano" refers to the group -CN.

[0059] The term "amino" refers to the group -NH2.

[0060] The term "oxo" refers to the group =O.

[0061] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number is shown subscripted after the symbol "C", the subscript more specifically limits the number of carbon atoms that a particular group may contain. For example, "C 1-4 alkyl" means straight-chain and branched-chain alkyl groups having 1 to 4 carbon atoms.

[0062] As used herein, the term "fluoroalkyl" is intended to encompass both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 fluoroalkyl" means encompassing C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0063] As used herein, the term "alkoxy" is an alkyl group that is connected to a part of the parent molecule via an oxygen atom, for example, referring to a methoxy group (-OCH3). For example, "C 1-3 alkoxy" means an alkoxy group having 1 to 3 carbon atoms.

[0064] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" denote a fluoroalkyl group as defined above that is connected via an oxygen bond (-O-). For example, "C 1-4 fluoroalkoxy" is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.

[0065] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number is shown subscripted after the symbol "C", the subscript more specifically limits the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6 cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms.

[0066] The present invention is intended to contain all isotopes of the atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. General examples include, but are not limited to, deuterium (D) and tritium (T) as isotopes of hydrogen. Isotopes of carbon include13 C and 14 C are included. The compounds of the present invention labeled with isotopes can be produced by using appropriate isotope-labeled reagents in place of the unlabeled reagents used otherwise, by conventional techniques generally known to those skilled in the art or by methods similar to those described herein.

[0067] As used herein, the phrase "pharmaceutically acceptable" means that within the scope of ordinary medical judgment, it is suitable for contact with human and animal tissues without causing excessive toxicity, irritation, allergic reaction, or other problems or complications, and provides a reasonable benefit / risk ratio, referring to compounds, substances, compositions, and / or dosage forms.

[0068] The compounds of formula (I) can form salts, and such salts are also within the scope of the present invention. Unless otherwise specified, references to the compounds of the invention are understood to include references to one or more of their salts. The term "salt" refers to acid salts and / or base salts formed by inorganic and / or organic acids and bases. Further, the term "salt" can include zwitterions (inner salts) when, for example, the compounds of formula (I) have both a basic moiety (e.g., an amine or pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferably, for example, acceptable metal salts and amine salts such that the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may also be useful, for example, in isolation or purification steps used in the manufacturing process, and thus are considered to be within the scope of the present invention. The salts of the compounds of formula (I) may be formed, for example, by reacting the compounds of formula (I) with a certain amount of acid or base (e.g., 1 equivalent), in a solvent, for example, by precipitating the salt or by subsequently lyophilizing the aqueous solution.

[0069] Examples of acid addition salts include acetates (e.g., acetates prepared from acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (prepared from hydrochloric acid), hydrobromides (prepared from hydrobromic acid), hydroiodides, maleates (prepared from maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (prepared from methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., prepared from sulfuric acid), sulfonates (e.g., those described herein), tartrates, thiocyanates, toluenesulfonates (e.g., tosylates), undecanoates, and the like.

[0070] Examples of base salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), barium, zinc, and aluminum salts, organic base salts, such as organic amines (e.g., trialkylamines (e.g., triethylamine), procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine), or similar pharmaceutically acceptable amines, and amino acid salts (e.g., arginine, lysine), etc. The basic nitrogen-containing group may be quaternized by reagents (e.g., lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and other groups). Preferred salts include hydrochloride, bisulfate, methanesulfonate, phosphate, or nitrate.

[0071] The compounds of formula (I) can be provided as amorphous solids or crystalline solids. The compounds of formula (I) can be provided as solids by lyophilization.

[0072] Furthermore, solvates (e.g., hydrates) of the compounds of formula (I) should also be considered within the scope of the present invention. The term "solvate" means a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both the solution phase and separable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0073] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0074] In addition, after being prepared, the compounds of formula (I) are isolated, purified, and obtained as a composition containing the compounds of formula (I) in an amount of 99% or more ( "substantially pure"), and then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered to be part of the present invention here.

[0075] "Stable compounds" and "stable structures" are intended to be sufficiently robust compounds that do not decompose even when isolated to useful purity from the reaction mixture or formulated into effective therapeutic agents. The present invention is intended to embody stable compounds.

[0076] The term "Helios inhibitor" refers to an agent that reduces the level of Helios protein and Helios activity level in cells and / or suppresses the Helios expression level in order to regulate the differentiation of Tregs. A Helios inhibitor can be a reversible or irreversible inhibitor.

[0077] As used herein, the "Helios" protein refers to a protein that is a member of the Ikaros family of zinc finger proteins. In humans, Helios is encoded by the IKZF2 gene. Also, Helios is also known as Ikaros family zinc finger 2, ANF1A2, ZNF1A2, ZNFN1A2, zinc finger protein, subfamily 1A, 2, and Ikaros family zinc finger protein 2. Members of this protein family include Ikaros, Helios, Aiolos, Eos, and Pegasus. The Helios protein used herein includes various isoforms, including isoforms 1-5 listed below. Isoform 1 (UniProt Q9UKS7-1) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 1) Isoform 2 (UniProt Q9UKS7-2) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP FHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 2) Isoform 4 (UniProt Q9UKS7-4) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 3) Isoform 6 (UniProt Q9UKS7-6) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHDS (SEQ ID NO: 4) Isoform 7 (UniProt Q9UKS7-7) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 5)

[0078] The above-mentioned Isoforms 1, 2, 4, 6, and 7 of “Helios” contain the degron, FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (underlined part). The degron is a part of a protein that plays a role in regulating the proteolysis rate.

[0079] The "Eos" protein used in this specification is encoded by the IKZF4 gene and is also known as Ikaros family zinc finger 4, ZNFN1A4, zinc finger protein, subfamily 1A, 4, Ikaros family zinc finger protein 4, and KIAA1782. The "Eos" protein includes isoforms encoded by the following two human isoforms 1 (Q9H2S9-1) and 2 (Q9H2S9-2). Isoform 1 (UniProt Q9H2S9-1) MHTPPALPRRFQGGGRVRTPGSHRQGKDNLERDPSGGCVPDFLPQAQDSNHFIMESLFCESSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAHHSLEPGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQPPPTIVVGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 7) Isoform 2 (UniProt Q9H2S9-2) MDSRYLQLQLYLPSCSLLQGSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAHHSLEPGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQPPPTIVVGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 8)

[0080] The above-mentioned "Eos" protein isoforms 1 and 2 contain the degron, FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (underlined part), which is identical to the degron of the "Helios" protein.

[0081] The "Ikaros" protein used in this specification is encoded by the IKZF1 gene. Also, Ikaros is also known as Ikaros family zinc finger 1, ZNFN1A1, zinc finger protein, subfamily 1A, 1, Ikaros family zinc finger protein 1, IK1, lymphoid transcription factor LyF-1, Hs.54452, PPP1R92, protein phosphatase 1, regulatory subunit 92, PRO0758, CVID13, and CLL-related antigen KW-6. The Ikaros protein includes isoforms encoded by amino acid sequences Q13422-1, Q13422-2, Q13422-3, Q13422-4, Q13422-7, and Q13422-8. Also, the Ikaros protein includes isoforms encoded by amino acid sequences Q13422-5 and Q13422-6.

[0082] The "Aiolos" protein used in this specification is encoded by the IKZF3 gene. Also, the Aiolos protein is also known as Ikaros family zinc finger 3, ZNFN1A3, zinc finger protein, subfamily 1A, 3, Ikaros family zinc finger protein 3, and AIO. The Aiolos protein includes isoforms encoded by amino acid sequences Q9UKT9-1, Q9UKT9-3, Q9UKT9-4, Q9UKT9-6, Q9UKT9-7, Q9UKT9-8, Q9UKT9-9, and Q9UKT9-14. Also, the Aiolos protein also includes isoforms encoded by amino acid sequences Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12, and Q9UKT9-13, Q9UKT9-15, and Q9UKT9-16.

[0083] The "Pegasus" protein used in this specification is also known as Ikaros family zinc finger 5, ZNFN1A5, zinc finger protein, subfamily 1A, 5, and Ikaros family zinc finger protein 5. Pegasus is encoded by the IKZF5 gene.

[0084] As used herein, the term "contact" refers to bringing into association with a specified moiety in vitro or in vivo. For example, "contacting" a Helios protein with a compound of formula (I) includes administering the compound of the invention to an individual or patient (e.g., a human) having the Helios protein, and also includes introducing the compound of formula (I) into, for example, a sample containing cells or a purified preparation containing the Helios protein.

[0085] As used herein, the terms "treat" and "treatment" refer to any intervention, method or administration of an active agent performed on a subject for the purpose of ameliorating, reducing, improving, inhibiting, delaying or suppressing the progression, onset, exacerbation or recurrence of a symptom, complication, condition or biochemical indication associated with a disease. In contrast, "prevent" or "prevention" refers to administration to a subject not suffering from a disease in order to prevent the occurrence of the disease. "Treat" and "treatment" do not include prevention or prophylaxis.

[0086] "Therapeutically effective amount" is intended to include the amount of a compound of the invention alone, or an amount of a compound of the claims in combination, or an amount of a compound of the invention in combination with other active ingredients, that is effective to lower the level of Helios protein and Helios activity levels in cells and / or to suppress Helios expression levels, or is effective for the treatment or prevention of viral infections and proliferative diseases (e.g., cancer).

[0087] As used herein, the term "cell" is intended to refer to cells in vitro, ex vivo or in vivo. In some embodiments, ex vivo cells can be part of a tissue sample excised from an organism (e.g., a mammal). In some embodiments, in vitro cells can be cells in cell culture. In some embodiments, in vivo cells are living cells in an organism (e.g., a mammal).

[0088] The term "patient" includes human and other mammalian subjects that receive either treatment or prophylactic treatment.

[0089] The term "subject" includes a human or any non-human animal. For example, the methods and compositions disclosed herein are used for the treatment of a subject suffering from cancer. Non-human animals include all vertebrates, such as mammals and non-mammals (non-human primates, sheep, dogs, cows, birds, amphibians, reptiles, etc.). In certain embodiments, the subject is a human.

[0090] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition, or vehicle, such as, for example, a liquid or solid diluent, excipient, processing aid (e.g., lubricants, magnesium stearate, calcium stearate or zinc stearate, or stearic acid), or solvent encapsulating agent, which is involved in the transport or delivery of a particular compound from one organ, or part of the body, to a different organ, or to a different part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation (i.e., including adjuvants, excipients or vehicles (e.g., diluents, preservatives, bulking agents, flow regulators, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispensing agents) depending on the nature of the method of administration and the dosage form) and not injurious to the patient.

[0091] The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one other pharmaceutically acceptable carrier.

[0092] (Usefulness) The compounds of formula (I) are useful for the treatment of cancer.

[0093] In one embodiment, the present invention provides a combination medicament of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, a stereoisomer or a tautomer thereof, and another therapeutic agent, which is used simultaneously, separately or sequentially in the treatment and / or prevention of a plurality of diseases or disorders related to the activity of the Helios protein. The combination medicament is used to reduce the Helios protein level, Helios activity level and / or Helios expression level in cells in order to regulate the differentiation of Tregs.

[0094] The compound of formula (I) and a pharmaceutical composition containing at least one compound of formula (I) are useful for the treatment or prevention of any disease or condition related to the activity of the Helios protein. Such diseases or conditions include viral infections and other infectious diseases (e.g., skin infections, GI infections, urinary tract infections, urogenital infections, systemic infections), and proliferative diseases (e.g., cancer). The compound of formula (I) and a pharmaceutical composition containing at least one compound of formula (I) can be administered to animals, preferably mammals (e.g., laboratory animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration can be used to deliver this compound or pharmaceutical composition to a patient. In one embodiment, the compound of formula (I) or a pharmaceutical composition containing at least the compound of formula (I) is administered orally. In other embodiments, the pharmaceutical composition containing the compound of formula (I) or at least the compound of formula (I) is administered parenterally.

[0095] The compound of formula (I) can selectively reduce the Helios protein level and Helios activity level in cells and / or suppress the Helios expression level in order to control Treg differentiation. For example, the compound of formula (I) is used to reduce the Helios activity level and / or inhibit the Helios expression level in a subject or cell that needs to selectively reduce the Helios protein level and Helios activity level and / or suppress the Helios expression level in order to control Treg differentiation, and the compound of formula (I) or a salt thereof can be administered in an inhibitory amount.

[0096] In one aspect, the compound of formula (I) is administered continuously prior to the administration of the immuno-oncology agent. In another aspect, the compound of formula (I) is administered concomitantly with the immuno-oncology agent. In yet another aspect, the compound of formula (I) is administered subsequent to the administration of the immuno-oncology agent.

[0097] In another aspect, the compound of formula (I) may be formulated together with the immuno-oncology agent.

[0098] Immuno-oncology agents include, for example, small molecule drugs, antibodies, or other biological molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is a humanized antibody or a human antibody.

[0099] In one aspect, the immuno-oncology agent is an agonist of a stimulatory receptor on T cells (including co-stimulation) or an antagonist of an inhibitory signal (including co-inhibition), both of which result in the amplification of an antigen-specific T cell response (often referred to as an immune checkpoint regulator).

[0100] Certain stimulatory and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory receptors, or co-inhibitory receptors, is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory receptors, or co-inhibitory receptors, is the TNF family of molecules that bind to the homologous TNF receptor family, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0101] In certain embodiments, the T cell response can be stimulated by a compound of formula (I) of the invention in combination with one or more of the following: (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor); e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin 1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation; e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H

[0102] For cancer treatment, other agents that can be combined with the compounds of formula (I) may include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds of formula (I) can be combined with an antagonist of KIR, such as lirilumab.

[0103] Still other agents for use in combination therapy include agents that inhibit or greatly reduce macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0104] In another aspect, the compounds of formula (I) are used with an agonistic agent that binds a positive costimulatory receptor, a blocking agent that attenuates signaling through an inhibitory receptor, an antagonist, and one or more agents that systemically increase the frequency of antitumor T cells, agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking the involvement of inhibitory receptors (e.g., the PD-L1 / PD-1 interaction), greatly reducing or inhibiting Treg cells (e.g., by using an anti-CD25 monoclonal antibody (e.g., daclizumab), or depletion of anti-CD25 beads in vitro), inhibiting metabolic enzymes such as IDO, or restoring / preventing T cell anergy or T cell depletion), and one or more of agents that cause innate immune activation and / or inflammation of the tumor portion.

[0105] In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, Yervoy (ipilimumab), or tremelimumab.

[0106] In another aspect, the immuno-oncology agent is a PD-1 antagonist, for example, an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, Opdivo (nivolumab), Keytruda (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). Although the specificity to PD-1 binding is questioned, pidilizumab (CT-011) may also be mentioned as an immuno-oncology agent. Another approach targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, designated AMP-224.

[0107] In another aspect, the immuno-oncology agent includes a PD-L1 antagonist, for example, an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO207 / 005874), and MSB0010718C (WO2013 / 79174).

[0108] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, for example, an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0109] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, for example, an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0110] In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable CD137 antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683).

[0111] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0112] In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0113] In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0114] In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0115] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an antagonistic CD27 antibody. Suitable CD27 antibodies include, for example, balstilimab.

[0116] In another aspect, the immuno-oncology agent (against B7H3) is MGA271 (WO11 / 109400).

[0117] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different time points, and also these therapeutic agents or at least two of them are administered in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering a single dosage form in which the ratio of each therapeutic agent is determined, or single dosage forms of each therapeutic agent to a patient. The sequential or substantially simultaneous administration of each therapeutic agent can be carried out, for example, by any suitable route such as the oral route, intravenous route, intramuscular route, and direct absorption through the mucosal membrane tissue, but is not limited thereto. The therapeutic agents can be administered by the same route or different routes. For example, the first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in this combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The above administration of the therapeutic agents can be combined with still other biologically active ingredients and non-drug therapies (such as surgery or radiation therapy) to perform combination therapy. When this combination therapy further includes a non-drug treatment, the non-drug treatment can be carried out at any appropriate time as long as a useful effect resulting from the combined action of the therapeutic agent and the non-drug treatment is achieved. For example, in a preferred case, this useful effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for several days or weeks, from the administration of the therapeutic agent.

[0118] The types of cancer that may be treated with the compounds of formula (I) include, but are not limited to, brain tumors, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer and bone cancer. Examples of such types of cancer include neuroblastoma, intestinal cancer (e.g., rectal cancer, colon cancer, familial adenomatous polyposis and hereditary non-polyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral primitive neuroectodermal tumor), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular cancer, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma.

[0119] For the treatment of diseases, disorders or conditions related to the Helios protein, one or more other pharmaceuticals or treatment methods (e.g., antiviral drugs, chemotherapeutic agents or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors) may be used in combination with the compounds of formula (I) as appropriate. The above agents may be combined with the present compound in a single dosage form, or the agents may be administered simultaneously or sequentially in different dosage forms.

[0120] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonic acids, nitrosoureas, and triazenes), such as uracil mustard, chloromethine, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0121] In the treatment of melanoma, suitable agents for use in combination with the compound of formula (I) include dacarbazine (DTIC), and optionally other chemotherapeutic agents (such as carmustine (BCNU) and cisplatin); the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; combinations of cisplatin, vinblastine, and DTIC, temozolomide, or yarboy TM The compound of formula (I) may also be combined with immunotherapeutic agents (such as cytokines (e.g., interferon α, interleukin 2, and tumor necrosis factor (TNF), etc.)) in the treatment of melanoma.

[0122] The compound of formula (I) may also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are somewhat similar in several respects to anti-viral vaccines used to prevent diseases caused by viruses (such as polio, measles, and mumps). Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.

[0123] Melanomas limited to the wrist or leg can also be treated using hyperthermic perfusion therapy in combination with an agent comprising one or more compounds of formula (I). In this treatment protocol, the circulation of the limb at the disease site is temporarily isolated from the rest of the body's circulation, and a high concentration of chemotherapeutic agent is injected into the artery of the affected limb, administering a high dose that could cause serious side effects if exposed to the internal organs to the tumor site. Usually, in this treatment, the body fluid is heated to 38.9 °C to 40 °C. Melphalan is the drug most frequently used in this chemotherapy. Another agent called tumor necrosis factor (TNF) can also be used.

[0124] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, antimetabolites (including, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, etc.), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0125] Suitable chemotherapeutic agents or other anti-cancer agents further include, for example, certain natural products and their derivatives (such as vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (taxol), mitomycin, deoxycoformycin, mitomycin C, L-asparaginase, interferon (especially IFNα), etoposide, and teniposide.

[0126] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and droloxifene.

[0127] In addition, suitable cytotoxic agents include, for example, epipodophyllotoxin; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes (such as cisplatin and carboplatin); biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0128] Other anticancer agents include antibody drugs such as trastuzumab (Herceptin®), antibodies against costimulatory molecules (such as CTLA-4, 4-1BB, and PD-1), or antibodies against cytokines (IL-10 or TGF-β).

[0129] Still other anticancer agents include anticancer agents that block immune cell migration, such as antagonists against chemokine receptors (such as CCR2 and CCR4).

[0130] Still other anticancer agents include anticancer agents that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0131] Anticancer vaccines include dendritic cell vaccines, synthetic peptide vaccines, DNA vaccines, and recombinant virus vaccines.

[0132] The pharmaceutical composition of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more important steps in a signal transduction pathway in the normal function of cancer cells, thereby causing apoptosis. Suitable STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., STI 571 (GLEEVEC®)); (ii) epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitors (IRESSA®, SSI-774)) and antibodies (Imclone: C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors (e.g., farnesyl transferase inhibitors (FTIs) (e.g., L-744,832 [Kohl et al., Nat. Med., 1(8):792-797 (1995)]); (iv) Akt family kinases or Akt pathway inhibitors (e.g., rapamycin (see, e.g., Sekulic et al., Cancer Res., 60:3504-3513 (200))); (v) cell cycle kinases inhibitors (e.g., flavopiridol and UCN-O1 (see, e.g., Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (203))); and (vi) phosphatidylinositol kinase inhibitors (e.g., LY294002 (see, e.g., Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994))). Alternatively, at least one STI and at least one compound of formula (I) may be formulated in separate pharmaceutical compositions. In certain embodiments of the present invention, at least one compound of formula (I) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) may be administered first, at least one STI may be administered first, or at least one compound of formula (I) and at least one STI may be administered simultaneously.Furthermore, when one or more compounds of formula (I) and / or STIs are used, the compounds can be administered in any order.

[0133] Furthermore, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I), optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent, in a pharmaceutically acceptable carrier, for treating a chronic viral infection in a patient.

[0134] Also provided is a method of treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.

[0135] In certain embodiments of the invention, at least one compound of formula (I) and at least one chemotherapeutic agent are administered to the patient either simultaneously or sequentially. In other words, at least one compound of formula (I) can be administered first, at least one chemotherapeutic agent can be administered first, or at least one compound of formula (I) and at least one chemotherapeutic agent can be administered simultaneously. Furthermore, when one or more compounds of formula (I) and / or chemotherapeutic agents are used, the compounds can be administered in any order. Similarly, any antiviral agent or STI can be administered at any point in time compared to the administration of the compound of formula (I).

[0136] Chronic viral infections that can be treated using the present combination therapy include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein - Barr virus (EBV), varicella - zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).

[0137] Suitable antiviral agents that may be considered for use in combination with the compound of formula (I) can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTI), non - nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, and other antiviral agents.

[0138] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C, the name being β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rodenosine (FddA). Representative and suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative and suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.

[0139] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different time points, and also these therapeutic agents or at least two therapeutic agents are administered in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering a single dosage form with a determined ratio of each therapeutic agent, or single dosage forms of each therapeutic agent to a patient. The sequential or substantially simultaneous administration of each therapeutic agent can be carried out, for example, by any suitable route such as the oral route, intravenous route, intramuscular route and direct absorption through the mucosal tissue membrane, but is not limited thereto. The therapeutic agents can be administered by the same route or different routes. For example, the first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in this combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The above administration of the therapeutic agents can be combined with still other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy) to perform combination therapy. When this combination therapy further includes non-pharmacological treatment, the non-pharmacological treatment can be carried out at any appropriate time point as long as a useful effect resulting from the combined action of the therapeutic agent and the non-pharmacological treatment is achieved. For example, in a preferred case, this useful effect is achieved even when the non-drug treatment is temporarily suspended, probably for several days or weeks, from the administration of the therapeutic agent.

[0140] (Pharmaceutical composition) The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I), formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more of the additional therapeutic agents described above.

[0141] The compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dosage effective for the intended treatment. The compounds of formula (I) and compositions of the compounds of formula (I) may be administered for any of the uses described herein by any suitable method (e.g., oral administration (e.g., tablets, capsules (including sustained release or timed release formulations thereof), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray dried dispersions), syrups, and emulsions); sublingual administration; buccal administration; parenteral administration (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., sterile aqueous or non-aqueous solutions or suspensions)); nasal administration including administration to the nasal membrane (e.g., inhalation sprays); topical administration (e.g., in the form of cream formulations or ointments); or rectal administration (e.g., in the form of suppositories)). These may be administered alone, but are generally administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical criteria.

[0142] For oral administration, the pharmaceutical composition may be, for example, in the form of tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably formulated in a unit dosage form having a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, more preferably about 0.5 to 100 mg. A suitable daily dosage for administration to humans or other mammals may vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0143] Any of the pharmaceutical compositions contemplated herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. The pharmaceutical compositions for oral administration can be manufactured according to any method known in the art of manufacturing pharmaceutical compositions for oral administration. To provide a pharmaceutically palatable formulation, the pharmaceutical compositions described herein can include at least one substance selected from sweetening agents, flavoring agents, coloring agents, lubricants, antioxidants, and preservatives.

[0144] Tablets can be manufactured, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic and pharmaceutically acceptable additive suitable for tablet manufacture. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binding agents (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Further, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract and to sustain the effect of the active ingredient over a longer period. Examples of water-soluble taste masking materials include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Examples of time-delay materials include, but are not limited to, ethylcellulose and cellulose acetate butyrate.

[0145] Hard gelatin capsules can be produced, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one inert solid diluent (for example, calcium carbonate, calcium phosphate, and kaolin).

[0146] Soft gelatin capsules can be produced, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one water-soluble carrier (for example, polyethylene glycol), and at least one oily medium (for example, peanut oil, liquid paraffin, and olive oil).

[0147] An aqueous suspension can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one additive suitable for the preparation of an aqueous suspension. Examples of additives suitable for the preparation of an aqueous suspension include, but are not limited to, for example, suspending agents (such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, alginic acid, polyvinyl pyrrolidone, tragacanth gum, and gum arabic), dispersing agents or wetting agents (such as naturally occurring phosphatides (such as lecithin), condensation products of alkylene oxides and fatty acids (such as polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (such as heptadecaethyleneoxy cetanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (such as polyethylene sorbitan monooleate)). Further, the aqueous suspension may include at least one preservative (such as ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (including, but not limited to, for example, sucrose, saccharin, and aspartame).

[0148] An oily suspension can be prepared, for example, by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil (such as peanut oil, olive oil, sesame oil, and coconut oil) or a mineral oil (such as liquid paraffin). The oily suspension can also contain at least one thickening agent (such as beeswax, solid paraffin, and cetyl alcohol). To provide a palatable oily suspension, at least one of the sweetening agents already described above and / or at least one flavoring agent can be added to the oily suspension. The oily suspension can further contain at least one preservative (including, but not limited to, for example, antioxidants (such as butylhydroxyanisole and α-tocopherol)).

[0149] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, for example, antioxidants (such as ascorbic acid). Furthermore, the dispersible powders and granules can also contain at least one excipient (including, but not limited to, for example, sweetening agents, flavoring agents, and coloring agents).

[0150] An emulsion of at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion containing the compound of formula (I) may be composed of known components by known methods. The oil phase can be provided, for example, but not limited to, vegetable oils (such as olive oil and peanut oil), mineral oils (such as liquid paraffin), and mixtures thereof. The oil phase may contain only an emulsifier, or may contain at least one emulsifier and a fat or an oil, or a mixture of both a fat and an oil. Suitable emulsifiers include, but are not limited to, for example, naturally occurring phosphatides (such as soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (such as sorbitan monooleate), and condensation products of partial esters and ethylene oxide (such as polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Additionally, the emulsifier, with or without a stabilizer, forms a so-called emulsifying wax, and the wax, together with the oil and the fat, forms a so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation. The emulsion may also contain a sweetening agent, a flavoring agent, a preservative, and / or an antioxidant. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, either alone or in combination with a wax; or other substances known in the art.

[0151] The compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be administered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, for example, sterile aqueous solutions, sterile water-in-oil microemulsions, and aqueous or oily suspensions containing acceptable vehicles and solvents (such as water, Ringer's solution, and sodium chloride isotonic solution).

[0152] Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules by using one or more carriers or diluents described for use in formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum, and / or various buffer solutions. Other adjuvants and methods of administration are known and widely known in the pharmaceutical field. Also, the active ingredient may be administered by injection as a composition with a suitable carrier (such as physiological saline, dextrose, or water), or cyclodextrin (i.e., Captisol), solubilizing co-solvent (i.e., propylene glycol), or solubilizing micelle (i.e., Tween 80).

[0153] Also, a sterile injectable preparation may be a sterile injection solution or suspension (such as a solution in 1,3-butanediol) in a non-toxic, parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents, those that may be used are water, Ringer's solution, and sodium chloride isotonic solution. Furthermore, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile fixed oil containing synthetic monoglycerides or diglycerides may be used. Furthermore, fatty acids such as oleic acid are used in injection preparations.

[0154] An oil-in-sterile-injection-water microemulsion can be produced, for example, as follows. 1) Dissolve at least one compound of formula (I) in an oil phase (for example, a mixture of soybean oil and lecithin), 2) combine the oil phase containing formula (I) with a mixture of water and glycerol, and 3) process the combination to form a microemulsion.

[0155] A sterile aqueous suspension or a sterile oily suspension can be produced according to methods known to those skilled in the art. For example, a sterile aqueous solution or a sterile aqueous suspension can be prepared using a non-toxic, parenterally acceptable diluent or solvent (such as 1,3-butanediol), and a sterile oily suspension can be produced using a sterile, non-toxic, acceptable solvent or suspension medium (such as a sterile fixed oil (for example, synthetic monoglycerides or diglycerides), and a fatty acid (such as oleic acid)).

[0156] Pharmaceutically acceptable carriers are formulated according to many factors that are well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can include, in addition to the active agent, many different components and additives, and such additional components are included in the formulation for various reasons, for example, for stabilization reasons such as active agents, binders, etc. known to those skilled in the art. An explanation of suitable pharmaceutically acceptable carriers and the factors in selecting them is described in various readily available literature, for example, Allen, L. V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0157] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate)), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and lanolin). Also, cyclodextrins (e.g., α-, β-, and γ-cyclodextrins, or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives)) may also be effectively used to enhance the delivery of the compounds of the formula described herein.

[0158] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to prepare agents for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may include conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifying agents, buffers, etc.). Tablets and pills can be additionally prepared using enteric coating agents. Such compositions may also include adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and fragrances).

[0159] For therapeutic use, the active compounds of the invention are combined with one or more adjuvants appropriate for the intended route of administration. When administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then may be tableted or encapsulated for convenient administration. Such capsules or tablets may include controlled release formulations and may be provided with the active compound dispersed in hydroxypropylmethylcellulose.

[0160] The amount of the compound to be administered and the dosing schedule for treating a medical condition using the compounds and / or compositions of the invention depend on various factors (e.g., age, weight, sex, the medical condition of the patient, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound utilized). Therefore, the dosing schedule may vary widely but can be determined in accordance with standard methods. A daily dose may suitably be between about 0.001 and 100 mg / kg of body weight, preferably between about 0.0025 and about 50 mg / kg of body weight, and most preferably between about 0.005 and 10 mg / kg of body weight. The daily dose may be administered 1 to 4 times a day. Other dosing schedules include once a week and once every two days cycles.

[0161] The pharmaceutical compositions of the invention suitably include at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally an additive selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Another composition of the invention includes a compound of formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0162] The present invention also includes a pharmaceutical kit useful, for example, in the treatment or prevention of Helios protein-related diseases or disorders and other diseases described herein, which comprises one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I). Such a kit may further optionally include one or more of the various conventional components of a pharmaceutical kit (e.g., a container containing one or more pharmaceutically acceptable carriers, another container), which will be readily apparent to those skilled in the art. Instructions in either an accompanying document or label indicating the amount of the components to be administered, dosing guidelines, and / or mixing guidelines for the components may also be included in the kit.

[0163] The dosing regimen of the compounds of the present invention will of course vary depending on known factors such as the pharmacodynamic properties of a particular agent and its method and route of administration; the species, age, sex, health status, medical condition, and body weight of the recipient; the nature and extent of the symptoms; the type of concomitant therapy; the frequency of treatment; the route of administration, the kidney and liver function of the patient, and the desired effect.

[0164] As a general guidance, the daily oral dose of each active ingredient, when used to obtain the intended effect, will range between about 0.001 to about 5000 mg / day, preferably about 0.01 to about 1000 mg / day, most preferably about 0.1 to about 250 mg / day. The most preferred dose for a constant rate infusion in intravenous administration ranges from about 0.01 to about 10 mg / kg / min. The compounds of formula (I) may be administered in a once-daily dose or the total daily dose may be administered in divided doses two, three, or four times a day.

[0165] The present compounds are generally appropriately selected for the intended dosage forms (e.g., oral tablets, capsules, elixirs, and syrups) and are administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) and are in accordance with conventional pharmaceutical standards.

[0166] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 200 mg of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is usually present in a weight of about 0.1 to 95% of the total weight of the composition.

[0167] Typical capsules for oral administration contain at least one compound of formula (I) (250 mg), lactose (75 mg), and magnesium stearate (15 mg). This mixture is sieved through a 60-mesh sieve and filled into No. 1 gelatin capsules.

[0168] Typical injection preparations are prepared by aseptically adding at least one compound of formula (I) (250 mg) to a vial, freeze-drying and sealing it aseptically. When in use, the contents of the vial are mixed with physiological saline (2 mL) to prepare an injection preparation.

[0169] The present invention includes within its scope pharmaceutical compositions containing, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I), either alone or in combination with a pharmaceutical carrier. The compounds of formula (I) can be used as appropriate alone, in combination with other compounds of formula (I), or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances).

[0170] Regardless of the administration route selected, the compounds of formula (I) and / or the pharmaceutical compositions of the present invention that can be used in a suitable hydrated form are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0171] The actual dosage level of the active ingredient in the pharmaceutical composition of formula (I) can be varied so as to be non-toxic to the patient and to contain an amount of the active ingredient effective to obtain a therapeutic effect for a particular patient, composition, and mode of administration.

[0172] The selected dosage level depends on various factors, including the activity of the specific compound of formula (I) or its ester, salt or amide used, the route of administration of the specific compound used, the administration time, the excretion or metabolism rate, the rate and extent of absorption, the treatment period, other agents, compounds and / or substances used in combination with the specific compound used, the age, sex, weight, symptoms, health status, as well as the medical history of the patient to be treated, and factors known in the medical field.

[0173] A physician or veterinarian having ordinary general knowledge in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of formula (I) used in the pharmaceutical composition at a level lower than the required amount to obtain a therapeutic effect, and gradually increase the dosage until the effect is obtained.

[0174] Generally, the appropriate daily dosage of the compound of formula (I) is the amount of the compound that is the lowest effective dosage to obtain a therapeutic effect. Such effective dosages are generally determined by the above factors. Generally, the dosage of the compound of formula (I) to a patient is about 0.01 to about 50 mg / kg body weight / day for oral, intravenous, intraventricular and subcutaneous administration.

[0175] If desired, the effective daily dosage of the active compound can be administered in divided dosages two, three, four, five, six or more times, at appropriate intervals throughout the day, in appropriate unit dosage forms. In certain embodiments of the present invention, the dosing is once a day.

[0176] Although it is possible to administer the compound of formula (I) alone, it is preferred to administer the compound as a pharmaceutical formulation (composition).

[0177] When the above-mentioned other therapeutic agents are used in combination with the compound of formula (I), they may be used, for example, in the amounts described in the Physicians' Desk Reference (PDR) or in amounts determined by those skilled in the art. In the methods of the present invention, the other therapeutic agents may be administered before, simultaneously with, or after the administration of the compounds of the present invention.

[0178] (Manufacturing method) The compounds of the present invention can be produced by many methods known to those skilled in the field of organic synthesis. The compounds of the present invention can be synthesized using the following methods, using synthetic methods known in the art of organic synthetic chemistry or similar synthetic methods evaluated by those skilled in the art. Preferred methods include, but are not limited to, the following methods. All documents cited in this specification are hereby incorporated by reference in their entirety.

[0179] The compounds of the present invention can be produced using the reactions and techniques described in this section. The reaction is carried out in a solvent suitable for the reagents and substances used and is appropriate for the transformation brought about. Also, in the description of the synthetic methods described below, all of the presented reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental time, and work-up method) are understood to be selected to be the standard conditions for the reaction, and this should be readily recognized by those skilled in the art. It is understood by those skilled in the field of organic synthesis that the functional groups present in various parts of the molecule must be compatible with the presented reagents and reactions. It is readily apparent to those skilled in the art that substituents compatible with the reaction conditions are so restricted, and alternative methods must be used. The reaction may also require a determination to change the order of synthetic steps or select a different specific reaction process in order to obtain the desired compound of the present invention. Also, in any synthetic route planning in this field, it is recognized that another important consideration is the selection of appropriate protecting groups to use for the protection of reactive functional groups present in the compounds described in the present invention. For the skilled experimenter, an authoritative document describing many alternatives for protecting groups is Protective Groups In Organic Synthesis by Greene and Wuts (Fourth Edition, Wiley & Sons, 2007).

[0180] The compound of formula (I) can be produced with reference to the method shown in the following scheme. As shown in the scheme, the final product is a compound having the same structural formula as formula (I). It is understood that any compound of formula (I) can be produced by this scheme by selecting appropriate reagents for appropriate substituents. Solvents, temperature, pressure and other reaction conditions can be easily selected by those skilled in the art. The starting materials are commercially available or can be easily produced by those skilled in the art. The components of the compound are defined as described herein.

[0181] The synthetic routes of the general compounds described in the present invention are illustrated in Schemes 1 to 5. Here, the substituents R1 and A are as defined above or are functional groups before being converted to the final substituents. The substituent L is a leaving group (e.g., a halide (preferably I, Br, or Cl) or triflate). The substituent M is a suitable coupling partner (e.g., boronic acid, boronic ester, or stannane). The substituent R is a carboxylic acid protecting group (e.g., tert-butyl, methyl, ethyl, or benzyl). As shown in Scheme 1, the general method for producing the compounds of the present invention can start from a suitable substituted isoindolinone 1. The leaving group L of 1 is converted to a suitable coupling partner M using conditions well-known to those skilled in the art or the methods described herein, and intermediate 2 can be obtained. Here, when M is boronic acid or boronic ester, 2 is coupled with a suitable substituted heterocycle 3 in the presence of a suitable base (e.g., cesium carbonate, potassium phosphate, or sodium bicarbonate) using a suitable palladium catalyst (e.g., Pd(PPh3)4 or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) by a Suzuki-Miyaura coupling reaction to obtain 4. Here, when M is stannane, 2 is coupled with a suitable substituted heterocycle 3 using a suitable catalyst (e.g., Pd(PPh3)4 or bis(triphenylphosphine)dichloropalladium(II) / CuI) by a Stille coupling reaction to obtain 4. Intermediate 4 can be converted to 5 by treatment with a protic acid (e.g., benzenesulfonic acid). Also, in some cases, 4 can be converted to 5 by treatment with a base (e.g., K2CO3, K3PO4, or LiHMDS). In other cases, intermediate 4 can cyclize to 5 spontaneously under the Suzuki-Miyaura coupling or Stille coupling conditions used.

Chemical formula

[0182] In some cases, it is advantageous for the coupling with heterocycle A to occur first in the synthesis procedure. In such cases, the leaving group L of 6 can be converted to a suitable coupling partner M using conditions well-known to those skilled in the art or the methods described herein, and intermediate 7 can be obtained. Here, when M is a boronic acid or boronic ester, 7 can be coupled with a suitable substituted heterocycle 3 by a Suzuki-Miyaura coupling reaction in the presence of a suitable base (e.g., cesium carbonate, potassium phosphate, or sodium bicarbonate) using a suitable palladium catalyst (e.g., Pd(PPh3)4 or dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)) to obtain 8. Here, when M is a stannane, 7 can be coupled with a suitable substituted heterocycle 3 by a Stille coupling reaction using a suitable catalyst (e.g., Pd(PPh3)4 or dichlorobis(triphenylphosphine)palladium(II) / CuI) to obtain 8. The methylbenzyl group can be brominated by the action of NBS in the presence of a radical initiator (e.g., light or AIBN) to obtain bromide 9. Bromide 9 can be condensed with 3-aminopiperidine-2,6-dione (10) in the presence of a base (e.g., diisopropylethylamine or triethylamine) to obtain 5.

Chemical formula

[0183] Also, bromide 9 can be condensed with 11 (where R = tert-butyl, methyl, ethyl, or benzyl) in the presence of a base (e.g., diisopropylethylamine or triethylamine) to obtain intermediate 12 as shown in Scheme 3. When R is tert-butyl, compound 5 can be synthesized from intermediate 12 by the method described in Scheme 1.

Chemical formula

[0184] Depending on which acid protecting group R is selected in intermediate 12, the conditions required for conversion to compound 5 are different (Scheme 4). For example, when R is methyl, ethyl, or benzyl, the base-induced cyclization of 12 is preferably directly converted from 12 to 5 using an appropriate base (e.g., LiHMDS) in an appropriate solvent (e.g., tetrahydrofuran). When R is tert-butyl, the acid-induced cyclization of 12 is preferably directly converted from 12 to 5 using an appropriate acid (e.g., benzenesulfonic acid) in an appropriate solvent (e.g., acetonitrile). In other cases, a method using two steps is preferred, in which free carboxylic acid 13 is first generated using conditions appropriate for a specific acid protecting group R. These are methods well known to those skilled in the field of organic synthesis. For example, when R is tert-butyl, acid hydrolysis using an appropriate acid (e.g., trifluoroacetic acid or hydrochloric acid) is preferred. When R is methyl, ethyl, or benzyl, base hydrolysis using an appropriate base (e.g., LiOH) is preferred. In other cases, when R is benzyl, it is better to deprotect by hydrogenolysis with a palladium catalyst. Once carboxylic acid 13 is generated, 13 is activated by the action of thionyl chloride / dimethylformamide or carbonyldiimidazole / dimethylaminopyridine and can be attacked intramolecularly by the primary amine of the pendant group to give 5.

Chemical formula

[0185] As shown in the above scheme, isoin-dolinone substituted with a suitable leaving group L is a useful intermediate in the synthesis of the compounds of formula (I). Where L is a leaving group (e.g., halide), the compound can be prepared as outlined in Scheme 5. First, the methylbenzyl group of intermediate 6 can be brominated by the action of NBS in the presence of a radical initiator (e.g., light or AIBN) to give bromide 14. Bromide 14 can be condensed with 3-aminopiperidine-2,6-dione (10) in the presence of a base (e.g., diisopropylethylamine or triethylamine) to give 15. In other cases, intermediate 15 can be converted to 5 by a method similar to the conversion from 1 to 4 (Scheme 1). In other cases, it is preferred to condense bromide 14 with intermediate 11 to give 16. Intermediate 16 can be converted to 5 by a method similar to those described in Scheme 1 and Scheme 4.

Chemical formula

[0186] (Example) The following examples illustrate specific embodiments of the present invention and are not intended to limit the scope of the present invention. Chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their general and customary meanings unless otherwise noted. Additional abbreviations used throughout the examples and the specification are defined above. Common intermediates are generally useful for the preparation of one or more of the examples. The compounds of the examples are identified by the examples and steps in which they are prepared (e.g., "1-A" represents Step A of Example 1), or are identified by the example only when the compound is the title compound of the example (e.g., "1" represents the title compound of Example 1). In some cases, alternative methods for preparing the intermediates or examples are described. Skilled chemists in the field of synthesis can frequently devise desirable alternative methods of preparation based on one or more considerations (e.g., shorter reaction times, less expensive starting materials, ease of operation and purification, higher yields, ease of catalysis, avoidance of toxic reagents, availability with special equipment, and reduction in the number of steps, etc.). The intention of describing alternative methods of preparation is to make the examples of the present invention easier to manufacture. In some cases, some of the functional groups in the schematic examples and claims may be replaced by biologically isosteric substitutions known to those skilled in the art (e.g., substitution of a carboxylic acid group with a tetrazole or phosphate moiety).

[0187]

Chem.

[0188] (HPLC conditions) Analytical HPLC Method 1: Waters XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; mobile phase A: 5:95 acetonitrile: water (0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (0.1% trifluoroacetic acid); temperature: 50 °C; gradient: elute from 0% B to 100% B over 3 minutes, then elute at 100% B for 0.50 minutes; flow rate: 1 mL / min; detection: MS and UV (220 nm)

[0189] Analysis HPLC method 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: 5:95 acetonitrile: water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile: water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: Elute from 0% B to 100% B over 3 minutes, then elute at 100% B for 0.50 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0190] Preparative HPLC method 1: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile: water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile: water (containing 10 mM ammonium acetate); Gradient: Elute at 15% B for 0 minutes, then elute from 15 to 50% B over 25 minutes, then elute at 100% B for 6 minutes; Flow rate: 20 mL / min; Column temperature: 25 °C; Fractions were collected by judging with the MS signal.

[0191] Preparative HPLC method 2: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile: water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile: water (containing 0.1% trifluoroacetic acid); Gradient: Elute at 0% B for 0 minutes, then elute from 0 to 40% B over 24 minutes, then elute at 100% B for 4 minutes; Flow rate: 20 mL / min; Column temperature: 25 °C; Fractions were collected by judging with the MS signal.

[0192] Preparative HPLC method 3: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile: water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile: water (containing 0.1% trifluoroacetic acid); Gradient: Elute at 0% B for 5 minutes, then elute from 0 to 25% B over 28 minutes, then elute at 100% B for 4 minutes; Flow rate: 20 mL / min; Column temperature: 25 °C; Fractions were collected by judging with the MS signal.

[0193] Fractionation HPLC method 4: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.1% trifluoroacetic acid); gradient: elution at 0% B for 3 minutes, then elution from 0 to 35% B over 30 minutes, and then elution at 100% B for 6 minutes; flow rate: 20 mL / min; column temperature: 25°C; fractions were collected by judging with MS signal. The fractions containing the product were combined and dried with a centrifugal evaporator. The substance was further purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile: water (containing 10 mM ammonium acetate); gradient: elution at 0% B for 0 minutes, then elution from 0 to 40% B over 28 minutes, and then elution at 100% B for 6 minutes; flow rate: 20 mL / min; column temperature: 25°C), and fractions were collected by judging with MS signal.

[0194] Preparative HPLC method 5: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.1% trifluoroacetic acid); gradient: elution at 4% B for 0 minutes, then elution from 4 - 44% B over 23 minutes, followed by elution at 100% B for 4 minutes; flow rate: 20 mL / min; column temperature: 25°C; fractions were collected based on MS signal determination. The fractions containing the product were combined and dried using a centrifugal evaporator. The substance was further purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile: water (containing 10 mM ammonium acetate); gradient: elution at 26% B for 0 minutes, then elution from 26 - 66% B over 20 minutes, followed by elution at 100% B for 4 minutes; flow rate: 20 mL / min; column temperature: 25°C), and fractions were collected based on MS signal determination.

[0195] Preparative HPLC method 6: Phenomenex Luna Axi C18, 100 mm x 30 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.1% trifluoroacetic acid); gradient: elution at 20% B for 2 minutes, then elution from 20 - 100% B over 11 minutes, followed by elution at 100% B for 2 minutes; flow rate: 25 mL / min; fractions were collected based on UV signal determination.

[0196] Fractionation HPLC method 7: Phenomenex Luna Axi C18, 100 mm x 30 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.1% trifluoroacetic acid); gradient: elution at 7% B for 2 minutes, then elution from 7 to 100% B over 10 minutes, and then elution at 100% B for 3 minutes; flow rate: 30 mL / min; fractions were collected by judging with UV signal.

[0197] Fractionation HPLC method 8: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile: water (containing 10 mM ammonium acetate); gradient: elution at 5% B for 0 minutes, then elution from 5 to 55% B over 20 minutes, and then elution at 100% B for 4 minutes; flow rate: 20 mL / min; column temperature: 25 °C; fractions were collected by judging with MS signal.

[0198] Fractionation HPLC method 9: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile: water (containing ammonium acetate); gradient: elution at 0% B for 0 minutes, then elution from 0 to 30% B over 23 minutes, and then elution at 100% B for 4 minutes; flow rate: 20 mL / min; column temperature: 25 °C; fractions were collected by judging with MS signal.

[0199] Fractionation HPLC method 10: Phenomenex Luna Axi C18, 100 mm x 30 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.1% trifluoroacetic acid); gradient: elution at 40% B for 3 minutes, then elution from 40 to 100% B over 4.5 minutes, and then elution at 100% B for 3 minutes; flow rate: 30 mL / min; fractions were collected by judging with UV signal.

[0200] Example 1 3-(1-Oxo-5-(quinolin-2-yl)isoindolin-2-yl)piperidine-2,6-dione [Chemical formula] Product 1A: tert-Butyl (S)-5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate To a suspension of tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (14.46 g, 60.6 mmol) in acetonitrile (231 mL) was added DIEA (20.2 mL, 115 mmol) at 0 °C. After stirring for 15 minutes, the reaction mixture was treated portionwise with solid methyl 4-bromo-2-(bromomethyl)benzoate (22 g, 57.7 mmol) over 5 minutes and stirred at 0 °C for 30 minutes. Then it was stirred at room temperature overnight, a reflux condenser was attached, and the reaction mixture was heated to 60 °C in an oil bath and maintained at the same temperature overnight. The reaction mixture was cooled to room temperature with stirring, and a precipitate formed after cooling to room temperature. The flask was added to a 0 °C water bath with stirring. After 30 minutes, the solid was collected by filtration, washed with a minimal amount of cold acetonitrile, air-dried, and 20.13 g (88% yield) was obtained as a white solid. Chiral analysis by HPLC showed that this substance had an ee > 98%. MS (ES): m / z = 397.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.76 - 7.71 (m, 1H), 7.68 - 7.62 (m, 2H), 6.22 (br s, 1H), 5.31 (br s, 1H), 4.91 (dd, J = 8.7, 6.3 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.51 - 4.40 (m, 1H), 2.47 - 2.10 (m, 4H), 1.44 (s, 9H)

[0201] Product 1B: tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate To a dried flask were added Product 1A (10.0 g, 25.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.67 g, 30.2 mmol), and potassium acetate (7.41 g, 76 mmol), and the flask was purged with nitrogen. The solid was suspended in dioxane (100 mL) and degassed with stirring for 5 minutes under a nitrogen stream. This reaction mixture was treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.737 g, 1.007 mmol), degassed for 5 minutes, sealed, and heated at 60 °C for 18 hours. The reaction mixture was diluted with EtOAc, filtered through celite, and further rinsed with EtOAc. The filtrate was concentrated and purified by ISCO (220 g silica gel column, 0%→20%B / DCM, B = 15% EtOH / EtOAc + 0.1% TEA) to afford Product 1B (9.9 g, 89% yield) as a white solid. MS(ES): m / z = 445.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.99 - 7.90 (m, 2H), 7.88 - 7.83 (m, 1H), 6.32 (br s, 1H), 5.36 (br s, 1H), 4.97 - 4.88 (m, 1H), 4.58 - 4.41 (m, 2H), 2.48 - 2.13 (m, 4H), 1.44 (s, 9H), 1.39 (s, 12H)

[0202] Example 1: 3-(1-oxo-5-(quinolin-2-yl)isoindolin-2-yl)piperidine-2,6-dione Product 1B (30 mg, 0.068 mmol) and 2-chloroquinoline (16.57 mg, 0.101 mmol) were added to a vial and purged with nitrogen. The solid was suspended in dioxane (540 μL), treated with cesium carbonate (2 M aqueous solution, 101 μL, 0.203 mmol), and degassed with stirring for 5 minutes under a nitrogen stream. This reaction mixture was treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.94 mg, 6.75 μmol), degassed for 5 minutes, sealed, and heated at 90 °C overnight. This reaction mixture was treated with celite, diluted with EtOAc, filtered, and concentrated. This mixture was divided into equal volumes in two screw-cap vials with Teflon liners, and acetonitrile (0.3 mL) and benzenesulfonic acid (10.7 mg, 0.068 mmol) were added to one of these vials. The reaction vial was sealed, placed in a preheated water bath at 90 °C, and maintained at the same temperature for 1.25 hours. This reaction mixture was concentrated under a nitrogen stream, diluted to 2 mL with DMF, purified by preparative HPLC method 1, and Example 1 (7.1 mg, 28% yield) was obtained. The optical purity was not determined. MS (ES): m / z = 372.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.58 - 8.49 (m, 2H), 8.44 (br d, J = 8.0 Hz, 1H), 8.25 (br d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.71 - 7.61 (m, 1H), 5.17 (br dd, J = 13.2, 4.5 Hz, 1H), 4.68 - 4.42 (m, 2H), 3.00 - 2.89 (m, 1H), 2.64 (br d, J = 18.3 Hz, 1H), 2.49 - 2.39 (m, 1H), 2.12 - 2.01 (m, 1H)

[0203] Example 2 3-(5-(4-Aminoisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] Product 1B (20.9 mg, 0.047 mmol), 3-bromoisoquinolin-4-amine (10 mg, 0.045 mmol), and PdCl2(dppf)2 (3.28 mg, 4.48 μmol) were added to a vial, followed by the addition of dioxane (0.5 mL). Cesium carbonate (2 M aqueous solution, 67 μL, 0.134 mmol) was added thereto, and the vial was sealed and purged with nitrogen. This mixture was heated by microwave at 140 °C for 15 minutes. After cooling, the reaction mixture was diluted with EtOAc, washed with brine, dried over MgSO4, and concentrated. A solution (1 mL) of benzenesulfonic acid (0.72 g / ACN (20 mL)) was added thereto, the vial was sealed, and heated by microwave at 140 °C for 8 minutes. The reaction mixture was diluted with DMSO (1 mL) and purified by preparative HPLC method 2 to obtain Example 2 (8.8 mg, 49% yield). The optical purity was not determined. MS (ES): m / z = 387.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.82 (s, 1H), 8.43 (br d, J = 8.4 Hz, 1H), 8.16 (br d, J = 7.8 Hz, 1H), 8.00 - 7.83 (m, 4H), 7.81 - 7.74 (m, 1H), 7.17 (s, 2H), 5.17 (br dd, J = 13.3, 5.0 Hz, 1H), 4.61 - 4.41 (m, 2H), 2.93 (br d, J = 11.8 Hz, 1H), 2.64 (br d, J = 15.7 Hz, 1H), 2.46 (br dd, J = 13.6, 4.1 Hz, 1H), 2.06 (br dd, J = 10.4, 5.2 Hz, 1H)

[0204] Examples 3 to 45 The compounds in Table 1 were produced according to the method described in Example 2 using appropriate aryl bromides or aryl chlorides. [Chemical formula]

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

[0205] Example 46 3-{5-[5-Amino-1-(2,2-dimethylpropyl)-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione

Chem.

[0206] Example 47 3-[5-(5-Amino-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0207] Example 48 N-{3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}acetamide

Chemical Structure

[0208] Product 48B: N-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}acetamide To a vial, product 48A (21.85 mg, 0.099 mmol), product 1B (44 mg, 0.099 mmol), Pd(PPh3)4 (11.44 mg, 9.90 μmol), and dioxane (1 mL) were added, and to this, NaHCO3 (0.5 M aqueous solution, 0.594 mL, 0.297 mmol) was added. The vial was sealed and purged with nitrogen. This mixture was heated by microwave at 150 °C for 15 minutes, the reaction mixture was concentrated to dryness, and 2 mL of benzenesulfonic acid solution (0.72 g / ACN (20 mL)) was added. The vial was sealed and heated by microwave at 130 °C for 7 minutes. The solvent was removed, and the resulting residue was dissolved in DMSO (2 mL). This mixture was filtered and purified by preparative HPLC method 4 to obtain Example 48 (4.8 mg, 11% yield). MS(ES): m / z = 430.3 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.47 (s, 1H), 8.44 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.59 (d, J = 17.4 Hz, 1H), 4.50 - 4.42 (m, 1H), 2.99 - 2.88 (m, 1H), 2.64 (br dd, J = 16.5, 2.7 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.29 (s, 3H), 2.10 - 2.01 (m, 1H)

[0209] Example 49 3-{5-[1-(Dimethylamino)isoquinolin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione

Chemical Structure

[0210] Example 49: Product 49A (20.5 mg, 0.099 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (55.1 mg, 0.124 mmol), Pd(PPh3)4 (11.46 mg, 9.92 μmol) and dioxane (1 mL) were added to a vial, followed by addition of NaHCO3 (0.5 M aqueous solution, 0.595 mL, 0.298 mmol). The vial was sealed and purged with nitrogen. The mixture was heated at 140 °C for 10 minutes by microwave, the reaction mixture was concentrated to dryness, treated with 2 mL of benzenesulfonic acid solution (0.72 g / ACN (20 mL)), and heated at 130 °C for 7 minutes by microwave. The solvent was removed, the resulting residue was dissolved in DMSO (2 mL), filtered, and purified by preparative HPLC method 5 to obtain Example 49 (15.4 mg, 38% yield). MS (ES): m / z = 415.4 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.43 (s, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 5.15 (dd, J = 13.4, 5.2 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.49 - 4.41 (m, 1H), 3.17 (s, 6H), 2.98 - 2.87 (m, 1H), 2.64 (br d, J = 17.7 Hz, 1H), 2.44 (qd, J = 13.2, 4.4 Hz, 1H), 2.12 - 2.00 (m, 1H)

[0211] Example 50 3-{5-[1-(Methylamino)isoquinolin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione

Chemical Structure

[0212] Example 50: This compound was prepared according to the general method for preparing 3-{5-[1-(dimethylamino)isoquinolin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione using Product 50A. MS (ES): m / z = 401.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.43 (s, 1H), 8.38 (br d, J = 7.8 Hz, 1H), 8.22 (br d, J = 8.1 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.70 - 7.62 (m, 2H), 7.52 (br t, J = 7.5 Hz, 1H), 5.16 (br dd, J = 13.0, 4.5 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.48 - 4.37 (m, 1H), 3.13 (br d, J = 2.5 Hz, 3H), 2.93 (br dd, J = 12.8, 4.2 Hz, 1H), 2.68 - 2.60 (m, 1H), 2.48 - 2.39 (m, 1H), 2.10 - 2.02 (m, 1H)

[0213] Example 51 3-{5-[5-(methylamino)-1,6-naphthyridin-7-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione [Chemical formula] Product 51A: 7-chloro-N-methyl-1,6-naphthyridin-5-amine 5,7-Dichloro-1,6-naphthyridine (250 mg, 1.256 mmol) and methanamine (40% aqueous solution, 2 mL) were added to a vial, the vial was sealed, and heated at 40 °C overnight. The reaction mixture was concentrated to dryness and purified by preparative HPLC method 7 to obtain Product 51A (121 mg, 50% yield). MS(ES): m / z = 194.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (dd, J = 4.2, 1.3 Hz, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.28 (br d, J = 3.5 Hz, 1H), 7.49 (dd, J = 8.4, 4.3 Hz, 1H), 6.95 (s, 1H), 2.96 (d, J = 4.5 Hz, 3H)

[0214] Example 51: 3-{5-[5-(methylamino)-1,6-naphthyridin-7-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione To a vial were added Product 1B (40 mg, 0.090 mmol), Product 51A (14.53 mg, 0.075 mmol), Pd(PPh3)4 (8.67 mg, 7.50 μmol) and dioxane (0.5 mL), followed by NaHCO3 (0.5 M aqueous solution, 0.450 mL, 0.225 mmol). The vial was sealed and purged with nitrogen. The mixture was heated by microwave at 130 °C for 15 minutes, diluted with EtOAc and brine. The organic layer was separated, dried over MgSO4 and concentrated. The resulting residue was dissolved in 1 mL of benzenesulfonic acid solution (0.72 g / ACN (20 mL)) and heated by microwave at 130 °C for 10 minutes. The solvent was removed, the resulting residue was dissolved in DMSO (2 mL), filtered, and purified by preparative HPLC method 8 to obtain Example 51 (9.0 mg, 30% yield). MS(ES): m / z = 402.3 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.00 - 8.94 (m, 1H), 8.68 (br d, J = 8.3 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.55 (dd, J = 8.3, 4.4 Hz, 1H), 5.16 (br dd, J = 13.3, 4.9 Hz, 1H), 4.58 (d, J = 17.3 Hz, 1H), 4.49 - 4.39 (m, 1H), 3.14 (br s, 3H), 2.99 - 2.87 (m, 1H), 2.69 - 2.59 (m, 1H), 2.48 - 2.38 (m, 1H), 2.12 - 2.00 (m, 1H)

[0215] Example 52 N-{3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}-N-methylacetamide [Chemical formula] Product 52A: N-(3-Chloroisoquinolin-1-yl)-N-methylacetamide To a vial, 3-chloro-N-methylisoquinolin-1-amine (13 mg, 0.067 mmol), DCM (5 mL), and acetic anhydride (344 mg, 3.37 mmol) were added, followed by Hunig's base (0.018 mL, 0.101 mmol), and the mixture was heated at 80 °C for 1 hour. The reaction mixture was concentrated, and the crude product 52A was used without purification.

[0216] Example 52: N-{3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}-N-methylacetamide To a vial were added product 1B (35 mg, 0.079 mmol), product 52A (12.0 mg, 0.051 mmol), Pd(PPh3)4 (7.59 mg, 6.56 μmol), and dioxane (0.5 mL), followed by NaHCO3 (0.5 M aqueous solution, 0.394 mL, 0.197 mmol). The vial was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 130 °C for 15 minutes, diluted with EtOAc and brine, the organic layer was separated, dried over MgSO4, filtered, and concentrated. The obtained residue was dissolved in 1 mL of benzenesulfonic acid solution (0.72 g / ACN (20 mL)), heated by microwave at 130 °C for 10 minutes, and then heated at 155 °C for 15 minutes. The reaction mixture was concentrated, dissolved in DMSO (2 mL), filtered, and purified by preparative HPLC method 8 to obtain Example 52 (6.5 mg, 22% yield). MS (ES): m / z = 442.9 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.10 - 10.99 (m, 1H), 8.68 (br d, J = 0.9 Hz, 1H), 8.44 (s, 1H), 8.36 (br d, J = 8.1 Hz, 1H), 8.20 (br d, J = 6.7 Hz, 1H), 8.03 (br d, J = 7.8 Hz, 1H), 7.96 - 7.86 (m, 2H), 7.85 - 7.76 (m, 1H), 5.16 (br dd, J = 13.3, 5.0 Hz, 1H), 4.63 - 4.55 (m, 1H), 4.51 - 4.42 (m, 1H), 3.47 (br s, 3H), 2.93 (br d, J = 3.5 Hz, 1H), 2.68 - 2.60 (m, 1H), 2.47 - 2.40 (m, 1H), 2.10 - 2.02 (m, 1H), 1.76 (br s, 3H)

[0217] Example 53 3-[5-(6-Amino-1,7-naphthyridin-8-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0218] Example 53: 3-[5-(6-Amino-1,7-naphthyridin-8-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione Product 1B (44.1 mg, 0.099 mmol), Product 53A (18.5 mg, 0.083 mmol), Pd(PPh3)4 (9.56 mg, 8.27 μmol), and dioxane (0.5 mL) were added to a vial, followed by NaHCO3 (0.5 M aqueous solution, 0.496 mL, 0.248 mmol). The vial was sealed and purged with nitrogen. The mixture was heated by microwave at 130 °C for 15 minutes, diluted with EtOAc and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The obtained residue was dissolved in 1 mL of benzenesulfonic acid solution (0.72 g / ACN (20 mL)) and heated by microwave at 130 °C for 15 minutes. The reaction mixture was concentrated, dissolved in DMSO (2 mL), filtered, and purified by preparative HPLC method 9 to obtain Example 53 (12.2 mg, 38% yield). MS(ES): m / z = 388.2 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.57 (dd, J = 3.9, 1.6 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.06 (dd, J = 8.6, 1.4 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 8.5, 3.9 Hz, 1H), 6.71 (s, 1H), 5.17 (dd, J = 13.4, 5.0 Hz, 1H), 4.57 (d, J = 17.3 Hz, 1H), 4.47 - 4.38 (m, 1H), 2.99 - 2.88 (m, 1H), 2.68 - 2.59 (m, 1H), 2.49 - 2.39 (m, 1H), 2.11 - 2.01 (m, 1H)

[0219] Example 54 3-[5-(3-Amino-5-methoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0220] Product 54B: 2-(2-Bromo-6-methoxyphenyl)acetonitrile To a vial were added product 54A (1150 mg, 4.11 mmol), potassium cyanide (401 mg, 6.16 mmol), and EtOH (10 mL), followed by water (3 mL). The mixture was stirred at 75 °C for 1 hour. The reaction was quenched with saturated aqueous NaHCO3, and the reaction mixture was diluted with EtOAc. The organic layer was separated, concentrated, and purified by ISCO (40 g column, elution solvent: 1 - 35% EtOAc / Hex) to obtain product 54B (799 mg, 86% yield). 1 H NMR (400 MHz, CDCl3) δ 7.25 - 7.18 (m, 2H), 6.89 (dd, J = 7.2, 2.0 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 2H)

[0221] Product 54C: 2-(Cyanomethyl)-3-methoxybenzonitrile To a vial were added product 54B (250 mg, 1.106 mmol), zinc dicyanide (78 mg, 0.664 mmol), Xantphos (19.20 mg, 0.033 mmol), and Pd2(dba)3 (30.4 mg, 0.033 mmol), followed by DMF (5 mL). The mixture was purged with nitrogen and heated at 130 °C for 1 hour. After cooling, the reaction was quenched with aqueous LiCl, and the reaction mixture was diluted with EtOAc. The organic layer was separated, concentrated, and purified by preparative HPLC method 10 to obtain product 54C (115 mg, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 8.1 Hz, 1H), 7.32 (dd, J = 7.8, 1.0 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 2H)

[0222] Product 54D: 1-Bromo-5-methoxyisoquinolin-3-amine Acetic acid (0.2 mL) and hydrogen bromide (30% / acetic acid, 329 mg, 1.22 mmol) were added to a vial and cooled to 0 °C. To this was added the product 54C (35 mg, 0.203 mmol), the vial was sealed, and stirred at 0 °C for 10 minutes. The ice bath was removed, the reaction mixture was stirred for 1 hour, and diluted with EtOAc (20 mL). Saturated aqueous NaHCO3 was added to quench the reaction. The organic layer was separated, concentrated, and the product 54D (48 mg, 84% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.7 Hz, 1H), 7.23 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 0.8 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 4.51 (br s, 2H), 3.99 (s, 3H)

[0223] Example 54: 3-[5-(3-Amino-5-methoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione To a vial were added the product 1B (39.5 mg, 0.089 mmol), the product 54D (18 mg, 0.071 mmol), Pd(PPh3)4 (8.22 mg, 7.11 μmol) and dioxane (0.5 mL), followed by NaHCO3 (0.5 M aqueous solution, 0.427 mL, 0.213 mmol). The vial was sealed and purged with nitrogen. This mixture was heated by microwave at 130 °C for 15 minutes. The reaction mixture was diluted with EtOAc and brine, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was dissolved in 2 mL of benzenesulfonic acid solution (0.72 g / ACN (20 mL)) and heated by microwave at 130 °C for 15 minutes. The solvent was removed, the resulting residue was dissolved in DMSO (2 mL), filtered, and purified by preparative HPLC method 8 to obtain Example 54 (5.1 mg, 17% yield). MS (ES): m / z = 417.1 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.96 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 7.01 (s, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.17 (br dd, J = 13.1, 4.9 Hz, 1H), 4.63 - 4.54 (m, 1H), 4.49 - 4.41 (m, 1H), 3.96 (s, 3H), 2.98 - 2.93 (m, 1H), 2.65 (br dd, J = 16.3, 2.0 Hz, 1H), 2.47 - 2.39 (m, 1H), 2.12 - 2.04 (m, 1H)

[0224] Examples 55 - 67 The compounds in Table 2 were prepared using appropriate aryl bromides or aryl chlorides according to the method described in Example 54 (Step 5).

Chemical formula

Table 10

Table 11

Table 12

[0225] Examples 70 - 76 The compounds in Table 3 were prepared using appropriate aryl bromides or aryl chlorides according to the method described in Example 2.

Chemical formula

Table 13

Table 14

[0226] Example 77 and Example 78 6-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridazine-3-carbonitrile (77) and 6-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridazine-3-carboxamide (78)

Chemical formula

[0227] Example 79 3-[5-(6-Amino-3-nitropyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0228] Examples 80 and 81 4-Amino-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyrimidine-5-carbonitrile (80) and 4-amino-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyrimidine-5-carboxamide (81) [Chemical formula] The title compounds were prepared using 4-amino-2-chloropyrimidine-5-carbonitrile according to the general method described in Example 79. Both products were isolated from the reaction mixture by preparative HPLC. Example 80: MS (ES): m / z = 363.0 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.46 (br d, J = 7.9 Hz, 1H), 8.14 - 7.90 (m, 2H), 7.86 (br d, J = 7.9 Hz, 1H), 5.08 (br dd, J = 13.1, 5.2 Hz, 1H), 4.63 - 4.51 (m, 1H), 4.46 - 4.38 (m, 1H), 2.93 - 2.82 (m, 1H), 2.63 (br dd, J = 14.8, 2.3 Hz, 1H), 2.46 - 2.32 (m, 1H), 2.04 (br dd, J = 12.1, 5.6 Hz, 1H) Example 81: MS(ES): m / z = 381.0 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.18 (br s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.56 (br s, 1H), 5.20 - 5.12 (m, 1H), 4.57 (br d, J = 17.3 Hz, 1H), 4.50 - 4.38 (m, 1H), 2.98 - 2.88 (m, 1H), 2.69 - 2.59 (m, 1H), 2.47 - 2.36 (m, 1H), 2.12 - 2.00 (m, 1H)

[0229] Example 82 (3S)-3-[5-(1-Aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0230] Product 82B: tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate To a dried round-bottom flask (250 mL) were added tert-butyl (S)-5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (9.07 g, 22.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.96 g, 27.4 mmol), and potassium acetate (6.72 g, 68.5 mmol), and the mixture was purged with nitrogen. The solid was suspended in dioxane (90 mL), degassed for 5 minutes with stirring under a nitrogen stream. The reaction mixture was treated with Pd(dppf)Cl2 (0.668 g, 0.913 mmol), degassed for 5 minutes, sealed, and heated at 60 °C for 18 hours under a nitrogen atmosphere. It was clearly shown by LCMS that complete conversion had occurred (both the ester and the acid were shown in the LCMS). The reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The filtrate was concentrated and purified by ISCO (220 g silica gel column, 0-20% B / DCM, B = 15% EtOH / EtOAc + 0.1% TEA) to give the product 82B (7.7 g, 17.33 mmol, 76% yield) as an off-white solid. 1 1H NMR was consistent with the product.

[0231] Product 82C: tert-butyl (S)-5-amino-4-(5-(1-aminoisoquinolin-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate Product 82B (7.47 g, 16.81 mmol), 3-bromoisoquinolin-1-amine (3 g, 13.45 mmol), PdCl2(dtbpf) (0.263 g, 0.403 mmol) and TEA (9.37 mL, 67.2 mmol) were added to a round-bottom flask (100 mL), followed by 2% aqueous TPGS solution (40 mL). The flask was sealed, purged with nitrogen, and heated at 40 °C overnight. By LCMS, the uncyclized product was shown as the main peak. The reaction mixture was diluted with 5% EtOH / EtOAc and filtered through celite. The viscous cake was washed thoroughly with 5% EtOH / EtOAc. Then the organic layer was separated, washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated and purified using a 220 g silica gel column (equilibration: 10% DCM / hexane, elution solvent: 0 - 80% B / DCM (B = 15% EtOH / EtOAc + 0.1% TEA)) to obtain Product 82C. 1 H NMR (400 MHz, methanol-d4) δ 8.21(s, 1H), 8.14(dd, J = 13.4, 8.2Hz, 2H), 7.86(d, J = 7.7Hz, 1H), 7.81(d, J = 7.7Hz, 1H), 7.67(t, J = 7.2Hz, 1H), 7.57 - 7.49(m, 2H), 5.05 - 4.96(m, 1H), 4.75(d, J = 17.4Hz, 1H), 4.63(d, J = 17.5Hz, 1H), 4.12 (q, J = 7.2Hz, 1H), 2.38 - 2.19(m, 4H), 1.41(s, 9H), 0.92(d, J = 6.7Hz, 1H)

[0232] Example 82: Product 82C (2.71 g, 5.88 mmol), and benzenesulfonic acid (1.862 g, 11.77 mmol) and acetic acid (75 mL) were added to a round-bottom flask, the flask was sealed, and heated at 100 °C. After 6.5 h, the flask was added to water at room temperature, after about 5 min, the precipitate was filtered, washed with acetic acid (80 mL) at room temperature, then washed with MeCN (40 mL) at room temperature, and then further washed with MeCN (40 mL). The solid was air-dried to obtain Example 82 (1.9 g, 79% yield). Enantiomeric purity measurement showed a chiral purity >99% e.e. MS(ES): m / z = 387.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.50 (br d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.96 - 7.91 (m, 2H), 7.78 - 7.70 (m, 2H), 5.16 (br dd, J = 13.0, 4.1 Hz, 1H), 4.62 - 4.54 (m, 1H), 4.51 - 4.42 (m, 1H), 3.00 - 2.87 (m, 1H), 2.69 - 2.60 (m, 1H), 2.49 - 2.36 (m, 1H), 2.10 - 2.03 (m, 1H)

[0233] Example 83 (3R)-3-[5-(1-Aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0234] Example 84 (3S)-3-[5-(1-Amino-4-ethoxyisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0235] Product 84B: 3-Bromo-4-ethoxyisoquinoline To a mixture of Product 84A (385 mg, 2.223 mmol) and 1-bromopyrrolidine-2,5-dione (475 mg, 2.67 mmol) in a round-bottom flask, DCE (30 mL) was added and the mixture was heated to 60 °C. After 16 hours, only a trace amount of starting material remained. Excess NBS (47.5 mg) was added and the reaction was carried out for an additional 1 hour. The reaction mixture was concentrated to dryness and purified by ISCO (24 g silica gel column, elution solvent: 0 - 100% ether / hexane) to obtain Product 84B (560 mg, 77%). 1 H NMR (400 MHz, chloroform-d) δ 8.86 (s, 1H), 8.13 (dd, J = 8.5, 0.8 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.77 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.70 - 7.63 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.60 (t, J = 7.1 Hz, 3H)

[0236] Product 84C: 3-Bromo-4-ethoxyisoquinoline 2-oxide A mixture of Product 84B (400 mg, 1.587 mmol) was dissolved in DCM (20 mL) at room temperature, 3-chloroperbenzoic acid (412 mg, 1.840 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness, diluted with EtOAc, washed with brine, dried over MgSO4, filtered, and then concentrated to dryness to obtain Product 84C (437 mg). MS (ES): m / z = 268.1 [M+H] + and 270.1 [M+H] +

[0237] Product 84D: 3-Bromo-1-chloro-4-ethoxyisoquinoline To the product 84C (200 mg, 0.746 mmol), phosphoryl chloride (3.49 mL, 37.3 mmol) was added, and the resulting mixture was stirred at room temperature. After 3 days, the product was shown as the main peak by LCMS. The reaction mixture was concentrated and purified by ISCO (24 g silica gel column, elution solvent: 2 - 100% DCM / hexane) to obtain the product 84D. 1 H NMR (400 MHz, chloroform - d) δ 8.31 (dt, J = 8.4, 0.9 Hz, 1H), 8.18 - 8.12 (m, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 4.31 - 4.23 (m, 2H), 1.65 - 1.58 (m, 3H)

[0238] Product 84E: 3 - Bromo - 4 - ethoxyisoquinolin - 1 - amine To a sealed tube were added the product 84D (40 mg, 0.140 mmol) and 28% aqueous NH3 solution (1.942 mL, 13.96 mmol), followed by the addition of MeOH (0.5 mL). The tube was sealed and heated at 140 °C for 2 hours. The product was shown by LCMS, but the reaction was not complete. The reaction mixture was purified by preparative HPLC method 1 to obtain the product 84E (13 mg).

[0239] Example 84: Product 84E (23.95 mg, 0.054 mmol), 3-bromo-4-ethoxyisoquinolin-1-amine (12 mg, 0.045 mmol), PdCl2(dtbpf) (1.464 mg, 2.246 μmol) and 1,4-dioxane (1 mL) were added to a vial, followed by the addition of Cs2CO3 (1 M aqueous solution) (0.135 mL, 0.135 mmol). The vial was sealed and purged with nitrogen. The mixture was heated at 40 °C for 16 h. By LCMS, the uncyclized product was shown as the main peak. The reaction mixture was diluted with EtOAc, washed with brine, the organic layer was separated and concentrated. The obtained crude material was dissolved in AcOH (0.5 mL), and PhSO3H (2 eq) was added. The reaction mixture was heated by microwave at 120 °C for 10 min, and the reaction mixture was concentrated to dryness. The obtained residue was dissolved in DMSO (1.8 mL) and purified by preparative HPLC method 1 to give Example 84 (1.9 mg, 10% yield). MS (ES): m / z = 431.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.29 - 8.20 (m, 3H), 8.05 - 7.98 (m, J = 8.2 Hz, 1H), 7.85 - 7.79 (m, J = 8.1 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 6.75 (br s, 2H), 5.14 (br dd, J = 13.5, 4.4 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.45 - 4.39 (m, 1H), 3.73 - 3.58 (m, 2H), 3.00 - 2.90 (m, 1H), 2.69 - 2.61 (m, 1H), 2.49 - 2.36 (m, 1H), 2.10 - 2.02 (m, 1H), 1.24 (t, J = 6.9 Hz, 3H)

[0240] The compounds in Table 5 were prepared according to the following general method. The aryl halides used were commercially available or obtained from the methods of the following prior literature. The optical rotation was not determined. General method 1: To a microwave vial (2 mL) were added aryl halide (1.0 equiv), product 1B (1.25 equiv), 3 mol% PdCl2(dtbpf), dioxane (1 mL), and 3 M aqueous K3PO4 (5 equiv). The vial was sealed and purged with nitrogen. The mixture was heated by microwave at 120 °C for 10 minutes, and the reaction mixture was diluted with EtOAc and brine. The organic layer was separated, dried over MgSO4, and concentrated. The crude material was transferred to another microwave vial (2 mL), PhSO3H (2 equiv) and MeCN (1 mL) were added, and the mixture was heated by microwave at 120 °C for 10 minutes. The mixture was concentrated, and the resulting residue was dissolved in DMSO (1.8 mL) and purified by preparative HPLC method 1.

Chemical formula

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

[0241] General method 2: It is the same as general method 1 except that acetic acid is used instead of acetonitrile for the cyclization reaction.

[0242] General method 3: It is the same as general method 1 except that PdCl2(dppf)2 is used as a catalyst instead of PdCl2(dtbpf).

[0243] Example 122 (3S)-3-[5-(1,8-Naphthyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical formula

[0244] Example 123 (S)-3-(5-(3-Aminoisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0245] Example 124 (S)-N-(1-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isoquinolin-3-yl)acetamide

Chemical Structure

[0246] Example 125 3-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}isoquinoline-1-carbonitrile

Chem.

[0247] Example 126 3-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}isoquinoline-1-carboxamide

Chem.

[0248] Example 127 (4S)-7-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-2H,3H,4H-pyrano[2,3-b]pyridin-4-yl acetate

Chemical Structure

[0249] Example 128 (4R)-7-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-2H,3H,4H-pyrano[2,3-b]pyridin-4-yl acetate [Chemical formula] Example 128 was prepared according to General Method 2 using (R)-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol as the aryl halide. The alcohol was acetylated in the last synthetic step (cyclization using AcOH as the solvent). MS (ES): m / z = 436.2 [M + H] + ; HPLC a T Ret = 1.30 min; 11H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.17 (br d, J = 8.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 5.93 (br t, J = 4.0 Hz, 1H), 5.13 (br dd, J = 13.1, 5.2 Hz, 1H), 4.58 - 4.52 (m, 1H), 4.50 - 4.40 (m, 2H), 4.38 - 4.31 (m, 1H), 2.96 - 2.87 (m, 1H), 2.67 - 2.59 (m, 1H), 2.48 - 2.36 (m, 1H), 2.28 - 2.15 (m, 1H), 2.08 (s, 3H)

[0250] Example 129 3-{5-[7-Chloro-4-(dimethylamino)isoquinolin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione

Chemical Structure

[0251] Product 129B: 1,7-Dichloro-N,N-dimethylisoquinolin-4-amine Product 128A (450 mg, 2.1 mmol) was dissolved in DMF (10 mL) at 0 °C, sodium hydride (152 mg, 6.34 mmol) was added all at once, and the mixture was stirred for 20 minutes. Then, iodomethane (0.224 mL, 3.59 mmol) was added dropwise. The reaction mixture was stirred for 1 hour, and the reaction was quenched with water. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over sodium sulfate. The product was purified by ISCO (silica gel column, elution solvent: 1 - 2% EtOAc / hexane) to obtain product 129B in a yield of 79%. 1 H NMR (400 MHz, chloroform - d) δ 8.20 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.85 (s, 1H), 7.61 (dd, J = 9.1, 2.0 Hz, 1H), 2.87 (s, 6H)

[0252] Example 129: Subsequent Suzuki coupling and cyclization occurred by General Method 1 using product 129B and product 1B. MS (ES): m / z = 449.2 [M + H] + ; HPLC a T Ret = 1.31 minutes; 1 H NMR (500 MHz, DMSO - d6) δ 11.04 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.87 (s, 1H), 7.83 (dd, J = 9.0, 2.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 5.19 (t, J = 1.0 Hz, 1H), 4.60 (d, J = 1.0 Hz, 1H), 4.47 (d, J = 1.0 Hz, 1H), 3.02 - 2.91 (m, 7H), 2.67 - 2.61 (m, 1H), 2.50 - 2.39 (m, 1H), 2.14 - 2.03 (m, 1H)

[0253] Example 130 1-Amino-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N,N-dimethylisoquinoline-4-carboxamide

Chem.

[0254] Product 130B: 1-Amino-3-chloroisoquinoline-4-carboxylic acid Product 130A (1.00 g, 3.90 mmol) and 28% aqueous NH3 (10.86 mL, 78 mmol) were added to a sealed tube, followed by the addition of MeOH (0.5 mL). The mixture was heated at 140 °C for 4 hours and then cooled. Most of the methanol was removed from the mixture using a rotary evaporator and diluted with ice water. The precipitate (product) was filtered and air-dried. The solid residue was purified by preparative HPLC method 2 to obtain Product 130B in 50% yield.

[0255] Product 130C: 1-Amino-3-chloro-N,N-dimethylisoquinoline-4-carboxamide Product 130B (30 mg, 0.135 mmol), HATU (64.0 mg, 0.168 mmol) and DMF (1 mL) were added to a sealed tube, followed by the addition of triethylamine (0.038 mL, 0.270 mmol). After 10 minutes, dimethylamine (6.68 mg, 0.148 mmol) was added, the tube was sealed and heated at 50 °C for 2 hours. The reaction mixture was diluted with 15% EtOH / EtOAc, washed with 10% aqueous LiCl solution, the organic layer was concentrated and purified using preparative HPLC method 2 to obtain product 130C (14 mg, 42% yield).

[0256] Example 130: Subsequent Suzuki coupling and cyclization occurred by general method 1 using product 130C and product 1B. MS (ES): m / z = 458.1 [M+H] + ; HPLC a T Ret = 0.92 min; 1 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.58 (br d, J = 7.9 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.83 - 7.77 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 5.20 - 5.14 (m, 1H), 4.62 - 4.52 (m, 1H), 4.48 - 4.39 (m, 1H), 3.00 - 2.93 (m, 1H), 2.92 (d, J = 5.5 Hz, 3H), 2.69 - 2.61 (m, 1H), 2.59 (d, J = 1.8 Hz, 3H), 2.48 - 2.40 (m, 1H), 2.12 - 2.03 (m, 1H)

[0257] Example 131 3-[5-(1-Amino-4-methylisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0258] Example 131: Subsequent Suzuki coupling and cyclization occurred by General Method 1 using Product 131A and Product 1B to obtain Example 131. MS (ES): m / z = 401.3 [M+H] + ; HPLC a T Ret = 1.24 min; 1 1H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 6.74 (s, 2H), 5.17 (dd, J = 13.5, 5.2 Hz, 1H), 4.54 (d, J = 17.5 Hz, 1H), 4.41 (d, J = 17.1 Hz, 1H), 2.99 - 2.90 (m, 1H), 2.67 - 2.60 (m, 1H), 2.48 - 2.41 (m, 1H), 2.40 (s, 3H), 2.10 - 2.02 (m, 1H)

[0259] Example 132 3-[5-(6-Amino-3-cyclopropylpyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0260] Example 132: To a microwave vial (2 mL), cyclopropylboronic acid (3.95 mg, 0.046 mmol), product 132A (15 mg, 0.031 mmol), PdCl2(dtbpf) (0.599 mg, 0.920 μmol), 1,4-dioxane (1 mL) and an aqueous K2CO3 solution (0.092 mL, 0.092 mmol) were added. The vial was sealed and purged with nitrogen. The mixture was heated by microwave at 130 °C for 10 minutes, the reaction mixture was diluted with EtOAc, washed with brine, the organic layer was separated and concentrated. The resulting crude product was dissolved in a PhSO3H / MeCN solution (0.228 M, 0.5 mL) and heated by microwave at 120 °C for 10 minutes. The mixture was concentrated to dryness and purified by preparative HPLC method 1 to give Example 132. MS (ES): m / z = 377.0 [M+H] + ; HPLC aT Ret = 1.05 min; 1 1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 8.5 Hz, 2H), 7.75 - 7.70 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 8.5 Hz, 1H), 5.89 - 5.78 (m, 2H), 5.16 (br dd, J = 13.3, 5.0 Hz, 1H), 4.53 (d, J = 1.0 Hz, 1H), 4.41 (d, J = 1.0 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.67 - 2.60 (m, 1H), 2.47 - 2.37 (m, 1H), 2.10 - 2.00 (m, 1H), 1.84 - 1.77 (m, 1H), 0.79 - 0.72 (m, 2H), 0.56 - 0.47 (m, 2H)

[0261] Example 133 3-[5-(6-Aminoisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0262] Example 134 N-{1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-6-yl}acetamide [Chemical formula] This compound was prepared as described in Example 133. Refer to the above product. MS (ES): m / z = 429.2 [M + H] + ; HPLC a T Ret = 0.98 min; 11H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.52 (d, J = 5.8 Hz, 1H), 8.46 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.65 (dd, J = 9.3, 1.7 Hz, 1H), 5.18 (dd, J = 13.1, 5.2 Hz, 1H), 4.60 (d, J = 1.0 Hz, 1H), 4.48 (d, J = 1.0 Hz, 1H), 3.01 - 2.90 (m, 1H), 2.65 (br d, J = 17.1 Hz, 1H), 2.50 - 2.38 (m, 1H), 2.15 (s, 3H), 2.12 - 2.05 (m, 1H)

[0263] Example 135 3-{5-[6-Amino-4-(chloromethyl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione

Chemical Structure

[0264] Product 135B: tert-butyl (S)-5-amino-4-(5-(6-amino-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate Product 135A (140 mg, 0.318 mmol) was dissolved in DCM (15 mL), cooled in an ice-water bath, and then thionyl chloride (0.461 mL, 6.36 mmol) was added dropwise. After 5 minutes, the ice-water bath was removed, the reaction mixture was warmed to room temperature, and after 1 hour, the reaction mixture was concentrated to dryness to obtain Product 135B (100% yield).

[0265] Example 135: Product 136B (30 mg) and a PhSO3H / acetonitrile solution (0.228 M, 1 mL) were added to a microwave vial (2 mL) and heated at 120 °C for 30 minutes by microwave. The reaction mixture was concentrated to dryness, and the obtained residue was purified by preparative HPLC Method 1 to obtain Example 135. MS (ES): m / z = 385.0 [M+H] + ; HPLC a T Ret = 1.02 min; 1 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.20 - 8.15 (m, 1H), 8.09 (br d, J = 8.5 Hz, 1H), 7.85 (br d, J = 7.9 Hz, 1H), 7.27 - 7.21 (m, 1H), 6.73 - 6.68 (m, 1H), 5.15 - 5.09 (m, 1H), 4.72 (s, 2H), 4.59 - 4.53 (m, 1H), 4.47 - 4.40 (m, 1H), 2.95 - 2.87 (m, 1H), 2.68 - 2.63 (m, 1H), 2.49 - 2.37 (m, 1H), 2.09 - 2.02 (m, 1H)

[0266] Example 136 3-(1-oxo-5-{5H,6H,7H,8H,9H-pyrido[2,3-b]azepin-2-yl}-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione

Chemical Structure

[0267] Example 137 3-[1-oxo-5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0268] Example 138 3-{5-[6-(2,2-Dimethylhydrazin-1-yl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione

Chemical Structure

[0269] Example 138: Example 138 was prepared according to General Method 1 using 2-chloro-6-(2,2-dimethylhydrazinyl)pyridine as the aryl halide. MS (ES): m / z = 380.3 [M+H] + ; HPLC a T Ret = 1.05 min; 1 1H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.29 (s, 1H), 8.24 (br d, J = 8.0 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.49 (br d, J = 7.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.15 (br dd, J = 13.4, 5.1 Hz, 1H), 4.54 (d, J = 17.2 Hz, 1H), 4.42 (d, J = 17.1 Hz, 1H), 3.00 - 2.92 (m, 1H), 2.68 - 2.59 (m, 1H), 2.57 - 2.53 (m, 6H), 2.49 - 2.39 (m, 1H), 2.09 - 2.01 (m, J = 10.9, 5.2 Hz, 1H)

[0270] Example 139 3-(5-(1H-Imidazo[4,5-b]pyridin-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0271] Example 140 3-(5-(6-Amino-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0272] Example 141 3-(5-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0273] Example 142 3-(5-(6-Aminopyrazin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0274] Example 143 3-(5-(2-Amino-6-methylpyrimidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0275] Example 144 3-(5-(4,6-Dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0276] Example 145 3-(5-(5-Chloro-3-hydroxyisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0277] Example 146 3-(5-(6-Methoxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0278] Example 147 3-(5-(6-Hydroxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0279] Example 148 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile

Chem.

[0280] Example 149 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isonicotinonitrile

Chemical Structure

[0281] Example 150 3-(5-(1-Amino-5,6,7,8-tetrahydroisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0282] Product 150B. 1-(1,3-dioxoisoindolin-2-yl)-5,6,7,8-tetrahydroisoquinoline 2-oxide To a solution of product 150A (23.4 mg, 0.084 mmol) / CH2Cl2 (420 μL) was added m-CPBA (29.0 mg, 0.168 mmol), and the mixture was stirred overnight at room temperature. Further, m-CPBA (29.0 mg, 0.168 mmol) and DCM (1 mL) were added, and the mixture was stirred overnight at room temperature. The reaction was quenched with a saturated aqueous Na2S2O3 solution, and the reaction mixture was diluted with CH2Cl2. The layers were separated, the aqueous phase was extracted with CH2Cl2 (3X), the organic layers were combined, dried over Na2SO4, filtered, concentrated to obtain product 150B (25 mg, 100%) as an off-white solid. ESI MS (M + H) + = 295.1

[0283] Product 150C. 2-(3-chloro-5,6,7,8-tetrahydroisoquinolin-1-yl)isoindoline-1,3-dione To a solution of product 150B (37.3 mg, 0.134 mmol) / POCl3 (1722 μL, 18.47 mmol), Et3N (18.66 μL, 0.134 mmol) was added, and the mixture was heated at 80 °C for 2 hours and then cooled to room temperature. This reaction mixture was carefully poured into ice-cooled saturated aqueous NaHCO3, and then extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4, filtered. The obtained crude material was dissolved in a minimum amount of CH2Cl2 and chromatographed. Purification by silica gel chromatography (ISCO, 12 g column, 30 mL / min, eluting with 0 - 100% EtOAc / hexane over 14 minutes, t r = 9 minutes) gave product 150C (3.8 mg, 10.94 μmol, 8.17% yield) as a white film. ESI MS (M+H) + = 313.2

[0284] Product 150D. 3-Chloro-5,6,7,8-tetrahydroisoquinolin-1-amine To a solution of product 150C (33.5 mg, 0.107 mmol) / EtOH (536 μL), triethylamine (16.42 μL, 0.118 mmol) was added, followed by hydrazine (3.70 μL, 0.118 mmol). This reaction mixture was stirred at room temperature, diluted with water, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4, filtered. The obtained crude material was dissolved in a minimum amount of CH2Cl2 and chromatographed. Purification by silica gel chromatography (ISCO, 12 g column, 30 mL / min, eluting with 0 - 100% EtOAc / hexane over 15 minutes, t r = 9 minutes) gave product 150D (9.7 mg, 0.050 mmol, 47.1% yield) as a white solid. ESI MS (M+H) + = 183.1

[0285] Example 150: To a vial were added product 150D (26.0 mg, 0.058 mmol), 3-chloro-5,6,7,8-tetrahydroisoquinolin-1-amine (9.7 mg, 0.053 mmol), Pd(PPh3)4 (6.14 mg, 5.31 μmol) and NaHCO3 (0.5 M aqueous solution, 0.319 mL, 0.159 mmol), followed by addition of dioxane (0.5 mL). The vial was sealed, evacuated, and filled with N2. The reaction mixture was heated by microwave at 130 °C for 15 minutes and extracted with EtOAc (2X). The combined organic layers were concentrated and dried under high vacuum, then dissolved in AcOH (0.5 mL), and benzenesulfonic acid (9.24 mg, 0.058 mmol) was added. The reaction vial was sealed and heated by microwave at 155 °C for 10 minutes. The reaction mixture was concentrated, and the crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.05% trifluoroacetic acid); gradient: elute at 0% B for 0 minutes, then elute from 0 to 50% B over 20 minutes, then elute at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C). The fractions containing the product were combined and dried in a centrifugal evaporator to obtain Example 150 (1.3 mg, 6%). ESI MS (M+H) + = 391.3; HPLC peak t r = 1.50 min; purity = 100% (analytical HPLC method 2)

[0286] Example 151 3-(5-(6-Amino-4,5-dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0287] Product 151B. 2-(1,3-dioxoisoindolin-2-yl)-3,4-dimethylpyridine 1-oxide To a solution of product 151A (63.8 mg, 0.253 mmol) / CH2Cl2 (1265 μL) was added m-CPBA (87 mg, 0.506 mmol), and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous Na2S2O3, diluted with CH2Cl2, the layers were separated, and the aqueous phase was extracted with CH2Cl2 (3X). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give product 151B (68 mg, 100%) as an off-white solid. ESI MS (M+H) + = 269.3

[0288] Product 151C. 2-(6-chloro-3,4-dimethylpyridin-2-yl)isoindoline-1,3-dione To a solution of product 151B (67.8 mg, 0.253 mmol) / POCl3 (3251 μL, 34.9 mmol), TEA (35.2 μL, 0.253 mmol) was added, and the mixture was heated at 80 °C for 2 h and then cooled to room temperature. The reaction mixture was carefully poured into ice-cooled saturated aqueous NaHCO3 and then extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4 and filtered. The resulting crude material was dissolved in a minimal amount of CH2Cl2 and chromatographed. Purification by silica gel chromatography (ISCO, 24 g column, 35 mL / min, eluting with 0 - 100% EtOAc / hexane over 15 min, t r = 9 min) gave product 151C (31 mg, 0.108 mmol, 42.8% yield) as a white solid. ESI MS (M + H) + = 287.1

[0289] Product 151D. 6-Chloro-3,4-dimethylpyridin-2-amine To a solution of product 151C (31 mg, 0.108 mmol) / EtOH (541 μL), triethylamine (16.58 μL, 0.119 mmol) was added, followed by hydrazine (3.73 μL, 0.119 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4 and filtered. The resulting crude material was dissolved in a minimal amount of CH2Cl2 and chromatographed. Purification by silica gel chromatography (ISCO, 12 g column, 30 mL / min, eluting with 0 - 100% EtOAc / hexane over 14 min, t r = 9.5 min) gave product 151D (5.8 mg, 0.035 mmol, 32.5% yield) as a white solid. ESI MS (M + H) + = 156.9

[0290] Example 151: tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (61.8 mg, 0.139 mmol), product 151D (21.8 mg, 0.139 mmol), Pd(PPh3)4 (161 mg, 0.139 mmol) and NaHCO3 (0.5 M aqueous solution, 0.835 mL, 0.418 mmol) were added to a vial, followed by dioxane (0.5 mL). The vial was sealed, evacuated and filled with N2. The reaction mixture was heated by microwave at 130 °C for 15 minutes and extracted with EtOAc (2X). The organic layers were combined, concentrated and dried under high vacuum. Then it was dissolved in AcOH (0.5 mL) and benzenesulfonic acid (22.02 mg, 0.139 mmol) was added. The reaction vial was sealed and heated by microwave at 155 °C for 10 minutes. The reaction mixture was concentrated and the crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile: water (containing ammonium acetate); gradient: eluted at 8% B for 2 minutes, then eluted from 8 - 48% B over 20 minutes, then eluted at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C). The fractions containing the product were combined and dried by a centrifugal evaporator to obtain Example 151 (2.2 mg, 4%). ESI MS (M+H) + = 365.2; HPLC peak t r = 1.35 min; purity = 100% (analytical HPLC method 2)

[0291] Example 152 6-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile

Chemical Structure

[0292] Example 153 3-(5-(6-Amino-5-methoxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0293] Product 153B. 2-(1,3-dioxoisoindolin-2-yl)-3-methoxy-4-methylpyridine 1-oxide To a solution of product 153A (243 mg, 0.906 mmol) / CH2Cl2 (4529 μL) was added m-CPBA (313 mg, 1.812 mmol), and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous Na2S2O3, diluted with CH2Cl2, the layers were separated, and the aqueous phase was extracted with CH2Cl2 (3X). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to obtain product 153B (257 mg, 100%) as an off-white solid. ESI MS (M+H) + = 285.3

[0294] Product 153C. 2-(6-chloro-3-methoxy-4-methylpyridin-2-yl)isoindoline-1,3-dione To a solution of product 153B (243 mg, 0.904 mmol) / POCl3 (11.628 mL, 125 mmol), TEA (0.126 mL, 0.904 mmol) was added, and the mixture was heated at 80 °C for 2 hours and then cooled to room temperature. This reaction mixture was carefully poured into ice-cooled saturated aqueous NaHCO3 and then extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4 and filtered. The resulting crude material was dissolved in a minimum amount of CH2Cl2 and chromatographed. Purification by silica gel chromatography (ISCO, 40 g column, 40 mL / min, eluting with 0 - 100% EtOAc / hexane over 15 minutes, t r = 9 minutes) gave product 153C (217 mg, 0.717 mmol, 79% yield) as a white solid. ESI MS (M+H) + = 303.1

[0295] Product 153D. 6-Chloro-3-methoxy-4-methylpyridin-2-amine To a solution of product 153C (217 mg, 0.717 mmol) / EtOH (3584 μL), triethylamine (110 μL, 0.789 mmol) was added, followed by hydrazine (24.75 μL, 0.789 mmol), and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with water and extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4 and filtered. The resulting crude material was dissolved in a minimum amount of CH2Cl2 and chromatographed. Purification by silica gel chromatography (ISCO, 40 g column, 40 mL / min, eluting with 0 - 100% EtOAc / hexane over 15 minutes, t r = 9.5 minutes) gave product 153D (85.1 mg, 0.493 mmol, 68.8% yield) as a white solid. ESI MS (M+H) + = 173.0

[0296] Example 153: To a vial were added product 1B (122 mg, 0.274 mmol), product 153D (43 mg, 0.249 mmol), Pd(PPh3)4 (28.8 mg, 0.025 mmol) and NaHCO3 (0.5 M aqueous solution, 1495 μL, 0.747 mmol), followed by dioxane (1246 μL). The vial was sealed, evacuated and filled with N2. The reaction mixture was heated at 130 °C for 15 min by microwave and extracted with EtOAc (3X). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give an orange residue. This was further dried under high vacuum and the crude material obtained was dissolved in AcOH (1.6 mL) and benzenesulfonic acid (43.3 mg, 0.274 mmol) was added. The reaction vial was sealed and heated at 155 °C for 10 min by microwave. The solvent was evaporated and the crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile: water (containing ammonium acetate); gradient: elution at 7% B for 0 min, then elution from 7 - 43% B over 30 min, then elution at 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C). The fractions containing the product were combined and dried by centrifugal evaporator to give Example 153 (4.9 mg, 5%). ESI MS (M+H) + = 381.2; HPLC peak t r = 1.22 min; purity = 100% (analytical HPLC method 2)

[0297] Example 154 3-(5-(4-((Benzyloxy)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0298] Product 154B. 4-((Benzyloxy)methyl)-2-chloropyridine To a solution of phenylmethanol (100 μL, 0.966 mmol) / DMF (966 μL) was added NaH (39.4 mg, 0.985 mmol), and the mixture was stirred at room temperature for 15 min, then product 156A (31.3 mg, 0.193 mmol) was added. After 2 h, the reaction was quenched with water, diluted with EtOAc, the layers were separated, and the aqueous phase was extracted with EtOAc (2X). The organic layers were combined, dried over Na2SO4, filtered, concentrated, and a residue was obtained. The obtained crude material was dissolved in a minimal amount of CH2Cl2 and chromatographed. Purification by silica gel chromatography (ISCO, 12 g column, 30 mL / min, eluting with 0 - 100% EtOAc / hexane over 19 min, t r = 8.5 min) gave product 154B (26.3 mg, 0.113 mmol, 58.3% yield). ESI MS (M + H) + = 234.4

[0299] Example 154: To a vial, tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (54.4 mg, 0.122 mmol), product 154B (26 mg, 0.111 mmol), Pd(PPh3)4 (12.86 mg, 0.011 mmol) and NaHCO3 (0.5 M aqueous solution, 668 μL, 0.334 mmol) were added, followed by dioxane (556 μL). The vial was sealed, evacuated, filled with N2, and heated at 130 °C for 15 minutes by microwave. The reaction mixture was extracted with EtOAc (3X), the organic layers were combined, dried over Na2SO4, filtered, concentrated to give an orange residue. This was further dried under high vacuum, and the obtained crude material was dissolved in AcOH (1.6 mL), and benzenesulfonic acid (19.36 mg, 0.122 mmol) was added. The reaction mixture was sealed and heated at 155 °C for 10 minutes by microwave. The reaction mixture was concentrated, and the crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.05% trifluoroacetic acid); gradient: eluted at 8% B for 0 minutes, then eluted from 8 - 48% B over 20 minutes, then eluted at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C), and the fractions containing the product were combined and dried by a centrifugal evaporator to give Example 154 (1.2 mg, 2%). ESI MS (M+H) + = 442.2; HPLC peak t r = 1.76 min; purity = 99% (analytical HPLC method 2)

[0300] Example 155 3-[5-(6-Methoxypyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione

Chemical Structure

[0301] Product 155B: Methyl 2-(bromomethyl)-4-iodobenzoate To a solution of product 155A (17.85 g, 64.7 mmol) in isopropyl acetate (211 mL) were added N-bromosuccinimide (14.96 g, 84 mmol) and AIBN (0.265 g, 1.616 mmol). The resulting suspension was placed in a preheated 70 °C bath, and nitrogen was continuously bubbled very slowly into this reaction mixture with a syringe (vented to a bubbler via another syringe) to remove bromine. The reaction mixture was heated at 70 °C for 5 h, cooled to room temperature, and concentrated. The resulting solid was stirred in ether, filtered to remove the solid, and washed with ether. The solid was removed, and the liquid containing ether was washed with a solution of sodium sulfite (5 g) / water (400 mL), separated into two washes, then washed with water and then brine. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting material was purified by Isco (2% EtOAc / Hex; eluted after 5 min and then eluted at a constant composition of 7%) to obtain the product containing impurities as a sticky solid. This material was suspended in minimal hexane, and the resulting solid was collected with a Buchner funnel to obtain product 155B (13.3 g, 58% yield). 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.8 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.72 - 7.67 (m, 1H), 4.89 (s, 2H), 3.96 (s, 3H)

[0302] Product 155C: 3-(5-Iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a suspension of 3-aminopiperidine-2,6-dione hydrochloride (5.15 g, 31.3 mmol) in acetonitrile (95 mL) was added Hunig's base (10.9 mL, 62.5 mmol). After stirring for 5 min, this reaction mixture was treated portionwise with solid product 157B (10.09 g, 28.4 mmol) over 5 min. After stirring at room temperature for 1 h, the reaction vessel equipped with a reflux condenser was slowly warmed to 70 °C in an oil bath and held at the same temperature for 2 days. The reaction mixture was cooled to room temperature and stirred overnight. The resulting precipitate was collected with a Buchner funnel and further washed with acetonitrile. The resulting solid was air-dried to obtain product 155C as a white powder (8.9 g, 85% yield).1 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.06 (s, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.4, 5.2 Hz, 1H), 4.49 - 4.41 (m, 1H), 4.36 - 4.28 (m, 1H), 2.98 - 2.84 (m, 1H), 2.70 - 2.56 (m, 1H), 2.43 - 2.29 (m, 1H), 2.06 - 1.96 (m, 1H)

[0303] Example 155: To a nitrogen-substituted vial containing a suspension of product 155C (18.5 mg, 50 μmol), 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (23.5 mg, 100 μmol), and XPhos Pd G2 (2.0 mg, 2.5 μmol) / DMF (500 μL, degassed), potassium phosphate tribasic (21.2 mg, 100 μmol) was added. The reaction mixture was stirred in a microwave reactor at 90 °C. After 3 hours, the reaction mixture was filtered, diluted with EtOAc (5 mL), washed with a saturated aqueous ammonium chloride solution (2 mL), the aqueous phase was back-extracted with EtOAc (5 mL), and the combined organic layers were concentrated under reduced pressure. The crude material was purified by preparative HPLC (column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: elution at 13% B for 0 minutes, then elution from 13 - 53% B over 20 minutes, followed by elution at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C) to obtain Example 155 (4.9 mg, 28% yield). LCMS (analytical HPLC method 1): T Ret = 1.44 min; m / z = 352.1 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.32 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.89 - 7.78 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.14 (br dd, J = 13.2, 4.9 Hz, 1H), 4.55 (d, J = 17.4 Hz, 1H), 4.42 (d, J = 17.1 Hz, 1H), 3.98 (s, 3H), 2.98 - 2.86 (m, 1H), 2.67 - 2.58 (m, 1H), 2.48 - 2.37 (m, 1H), 2.10 - 1.98 (m, 1H)

[0304] Examples 156 and 157 3-[5-(1-Methoxyisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (156) and 3-[1-oxo-5-(1-oxo-1,2-dihydroisoquinolin-3-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (157) [Chemical Structure] Product 156A: 3-Bromo-1-methoxyisoquinoline A suspension of 1,3-dibromoisoquinoline (215 mg, 750 μmol) and sodium methoxide (40.5 mg, 750 μmol) in toluene (3.0 mL) was stirred in a heater block at 110 °C, and additional sodium methoxide (203 mg, 3750 μmol) was added in portions at 1.5 h and 5 h. After a total of 20.5 h, the reaction mixture was cooled to room temperature, quenched with water (0.1 mL), and concentrated under reduced pressure. The resulting crude product was dissolved in a small amount of DCM, adsorbed onto a plug of SiO2, and purified by flash chromatography (SiO2, 40 g column, isocratic 1% EtOAc / hexane, 40 mL / min) to give Product 156A as a white solid (160 mg, 90% yield). MS (ES): m / z = 238.1, 240.1 [M+H] + ; 11H NMR (500 MHz, chloroform-d) δ 8.19 (dd, J = 8.3, 1.0 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.53 (ddd, J = 8.3, 5.9, 2.3 Hz, 1H), 7.44 (d, J = 0.8 Hz, 1H), 4.14 (s, 3H)

[0305] Examples 156 and 157: To a solution of Product 156A (40.0 mg, 0.168 mmol) and Product 1B (149 mg, 0.336 mmol) in 1,4 - dioxane (0.50 mL) was added a solution of potassium carbonate (46.4 mg, 0.336 mmol) in water (336 μL). The reaction vessel was evacuated three times and filled with nitrogen, then PdCl2(dppf) (6.2 mg, 8.4 μmol) was added. The resulting mixture was stirred at 100 °C. After 45 minutes, the reaction mixture was filtered, diluted with EtOAc (5 mL), and washed with a saturated aqueous ammonium chloride solution (2 mL). The aqueous phase was back - extracted with EtOAc (5 mL), and the combined organic layers were concentrated under reduced pressure. The resulting crude intermediate was suspended in acetonitrile (840 μL), and then benzenesulfonic acid (26.6 mg, 168 μmol) was added. The mixture was stirred at 90 °C. After 3 hours, benzenesulfonic acid (26.6 mg, 168 μmol) was added again, and stirring was resumed at 90 °C. After a total of 4.5 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by preparative HPLC (column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile: water (containing ammonium acetate); gradient: elution at 7% B for 0 minutes, then elution from 7 - 69% B over 30 minutes, then elution at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C) to give Example 156 (14.8 mg, 22% yield). LCMS (Analytical HPLC Method 1): T Ret = 1.9 min; m / z = 402.2 [M + H] + ; 11H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.45 (s, 1H), 8.40 (br d, J = 8.4 Hz, 1H), 8.20 (br d, J = 8.2 Hz, 1H), 8.17 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 5.15 (br dd, J = 13.5, 4.7 Hz, 1H), 4.58 (d, J = 17.1 Hz, 1H), 4.44 (d, J = 16.9 Hz, 1H), 4.21 (s, 3H), 2.98 - 2.88 (m, 1H), 2.67 - 2.59 (m, 1H), 2.47 - 2.39 (m, 1H), 2.10 - 1.99 (m, 1H) Example 157 was isolated from the same product (14.3 mg, 22% yield). LCMS (Analytical HPLC method 1): T Ret = 1.26 min; m / z = 388.2 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 11.65 (br s, 1H), 11.03 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.54 (ddd, J = 8.1, 5.1, 3.1 Hz, 1H), 7.04 (s, 1H), 5.13 (br dd, J = 13.4, 4.7 Hz, 1H), 4.54 (d, J = 17.5 Hz, 1H), 4.42 (d, J = 17.6 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.68 - 2.60 (m, 1H), 2.49 - 2.39 (m, 1H), 2.11 - 2.00 (m, 1H)

[0306] Example 158 3-(5-{1-Benzyl-1H-pyrrolo[3,2-c]pyridin-6-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione

Chem.

[0307] Example 158: To a solution of Product 158A (20.1 mg, 0.083 mmol) and Product 1B (55.2 mg, 0.124 mmol) in 1,4-dioxane (0.50 mL) was added a solution of potassium carbonate (22.9 mg, 0.166 mmol) in water (0.33 mL). The reaction vessel was evacuated three times and filled with nitrogen, then XPhos Pd G2 (3.3 mg, 4.14 μmol) was added and the mixture was stirred at 100 °C. After 4.5 hours, the reaction mixture was filtered, diluted with EtOAc (5 mL), and washed with a saturated aqueous ammonium chloride solution (2 mL). The aqueous phase was back-extracted with EtOAc (5 mL), and the combined organic layers were concentrated under reduced pressure. The resulting crude residue was suspended in acetonitrile (1.0 mL), then benzenesulfonic acid (26.2 mg, 0.166 mmol) was added and the mixture was stirred at 90 °C. After 15 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the crude material was purified by preparative HPLC (column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile: water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile: water (containing 0.05% trifluoroacetic acid); gradient: elution at 4% B for 0 minutes, then elution from 4 - 44% B over 20 minutes, then elution at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C) to obtain Example 158 (15.9 mg, 40% yield). LCMS (Analytical HPLC Method 1): T Ret = 1.25 min; m / z = 451.2 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.20 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.14 (br d, J = 8.3 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.40 - 7.23 (m, 5H), 7.02 (d, J = 2.8 Hz, 1H), 5.68 (s, 2H), 5.15 (dd, J = 13.1, 5.1 Hz, 1H), 4.59 (d, J = 17.9 Hz, 1H), 4.47 (d, J = 17.3 Hz, 1H), 2.98 - 2.86 (m, 1H), 2.69 - 2.58 (m, 1H), 2.48 - 2.38 (m, 1H), 2.10 - 2.01 (m, 1H)

[0308] Examples 159 - 161 The compounds in Table 6 were prepared using an appropriate aryl chloride according to the method described in Example 157.

Chemical formula

Table 23

[0309] Examples 162 - 166 The compounds in Table 7 were prepared using an appropriate aryl bromide according to the method described in Example 144.

Chemical formula

Table 24

[0310] Example 167 N-(6-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,4-dimethylpyridin-2-yl)acetamide

Chemical formula

[0311] Example 168 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridine-3,5-dicarbonitrile

Chemical Structure

[0312] Example 168: To a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-3,5-dicyanopyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg, 1.086 mmol) in acetonitrile (5 mL) was added benzenesulfonic acid (172 mg, 1.086 mmol). The reaction mixture was sealed and irradiated in a microwave reactor at 120 °C for 30 minutes. Monitored by LCMS, after completion of the reaction, it was cooled to room temperature and a solid precipitated. The obtained solid was filtered through a Buchner funnel and dried in vacuo to give 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridine-3,5-dicarbonitrile (195 mg, 0.484 mmol, 44.6%) as a pale yellow solid. LCMS: Column: Kinetex XB-C18 (75x30) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate; Mobile phase B: ACN; Flow rate: 1.0 mL / min; Purity = 96.95% (RT = 1.07 min) HPLC: Column: Kinetex Biphenyl (100 X 4.6) mm, 2.6 μm, Mobile phase A: 0.05% aqueous TFA; Mobile phase B: ACN; Flow rate: 1.0 mL / min; Purity = 95.9% (RT = 5.95 min) 1 1H-NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.62 (s, 1H), 8.10 (m, 2H), 8.00 (s, 1H), 7.90 (d, J = 1.20 Hz, 2H), 5.17 (dd, J = 5.20, 13.20 Hz, 1H), 4.56 (d, J = 17.60 Hz, 1H), 4.43 (d, J = 17.60 Hz, 1H), 2.89 - 2.98 (m, 1H), 2.53 - 2.68 (m, 1H), 2.41 - 2.50 (m, 1H), 2.03 - 2.08 (m, 1H)

[0313] Example 169 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoronicotinonitrile [Chemical formula] Product 169A: tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate To a stirred solution of tert-butyl (S)-5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (5 g, 12.59 mmol) in 1,4-dioxane (80 mL), potassium acetate (3.71 g, 37.8 mmol) and bis(pinacolato)diboron (4.79 g, 18.88 mmol) were added under a nitrogen atmosphere. The mixture was degassed with N2 gas for 10 minutes, and then PdCl2(dppf)-CH2Cl2 adduct (1.028 g, 1.259 mmol) was added. The resulting reaction mixture was heated at 80 °C for 4 hours, cooled to room temperature, filtered through celite, and the filtrate was diluted with EtOAc (450 mL) and water (200 mL). The layers were separated. The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product (15 g). This was purified by silica gel column chromatography (Isolera, eluent: 50 - 60% EtOAc / hexane) to give tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (4.6 g, 8.38 mmol, 66.6%) as a pale red solid.

[0314] Product 169B: tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a sealed tube, to a stirred solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (500 mg, 1.125 mmol) / 1,4-dioxane (4 mL) was added 2-amino-6-chloro-5-fluoronicotinonitrile (174 mg, 1.013 mmol) at room temperature, followed by potassium carbonate (389 mg, 2.81 mmol) / water (0.8 mL), and the mixture was degassed with nitrogen for 15 minutes. To this was added PdCl2(dppf)-CH2Cl2 adduct (45.9 mg, 0.056 mmol) at room temperature under a nitrogen atmosphere, and the mixture was degassed again for 5 minutes. The tube was sealed, heated at 100 °C, and stirred for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (650 mg). This was purified by silica gel column chromatography (Isolera, eluent: 50 - 80% EtOAc / petroleum ether) to obtain tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 0.604 mmol, 53.6%) as a pale yellow solid.

[0315] Example 169: In a microwave vial, to a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 0.662 mmol) / acetonitrile (3 mL) was added benzenesulfonic acid (105 mg, 0.662 mmol), the reaction vial was sealed, and irradiated in a microwave reactor at 120 °C for 30 minutes. The progress of the reaction was monitored by LCMS, and after completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product (400 mg). This was purified by preparative HPLC to obtain 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoronicotinonitrile formate (56 mg, 0.127 mmol, 19.20% yield) as an off-white solid. Fractional HPLC method details: Column: YMC C18 (250 X 20) mm, 5 μm, Mobile phase A: 0.1% formic acid aqueous solution, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: HPLC: Column: Kinetex Biphenyl (100 X 4.6) mm, 2.6 μm, Mobile phase A: 0.05% TFA aqueous solution, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 7.243 min; Purity = 96.46% LCMS: Column: Kinetex XB-C18 (75 x 30) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 1.11 min, Purity = 98.01%; 1 HNMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.01 (d, J = 10.80 Hz, 1H), 7.94 (s, 1H), 7.85 (t, J = 9.60 Hz, 2H), 5.16 (dd, J = 5.20, 13.20 Hz, 1H), 4.55 (d, J = 17.60 Hz, 1H), 4.41 (d, J = 17.60 Hz, 1H), 2.89 - 2.98 (m, 1H), 2.60 - 2.68 (m, 1H), 2.41 - 2.50 (m, 1H), 2.03 - 2.08 (m, 1H)

[0316] Example 170 3-(5-(6-Amino-4-phenylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0317] Example 170: To a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-4-phenylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (125 mg, 0.257 mmol) / acetonitrile (1.6 mL) in a microwave vial, benzenesulfonic acid (40.6 mg, 0.257 mmol) was added, the vial was sealed, and irradiated at 120 °C for 30 minutes in a microwave reactor. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product (350 mg). This was purified by preparative HPLC to obtain 3-(5-(6-amino-4-phenylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (13 mg, 0.030 mmol, 11.8%) as an off-white solid. Fractionation and purification method details: Column: YMC C18 (250 X 20) mm, 5 μm, Mobile phase A: 0.1% formic acid aqueous solution, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: HPLC: Column: Kinetex Biphenyl (100 X 4.6) mm, 2.6 μm, Mobile phase A: 0.05% TFA aqueous solution, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 5.248 min; Purity = 96.4%; LCMS: Column: Kinetex XB-C18 (75 x 30) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 1.10 min, Purity = 92.45%; 1 HNMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.30 (s, 1H), 8.23 (d, J = 8.00 Hz, 1H), 7.79 - 7.84 (m, 3H), 7.51 - 7.56 (m, 4H), 6.84 (s, 1H), 6.45 (bs, 2H), 5.15 (dd, J = 5.20, 13.20 Hz, 1H), 4.55 (d, J = 17.60 Hz, 1H), 4.42 (d, J = 17.60 Hz, 1H), 2.88 - 2.96 (m, 1H), 2.65 - 2.69 (m, 1H), 2.39 - 2.43 (m, 1H), 2.02 - 2.05 (m, 1H)

[0318] Example 171 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile

Chemical formula

Chemical formula

[0319] Product 171C: tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate A solution of well-stirred tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (600 mg, 1.350 mmol) and 6-amino-2-chloro-4-(trifluoromethyl)nicotinonitrile (171B, 299 mg, 1.350 mmol) in a microwave vial (30 mL) was added with an aqueous sodium bicarbonate solution (284 mg, 3.38 mmol, 2 M, 1 mL) at ambient temperature. The resulting reaction mixture was bubbled with nitrogen gas for 10 minutes for degassing, and then tetrakis(triphenylphosphine)palladium(0) (46.8 mg, 0.041 mmol) was added to this reaction mixture, which was then heated at 120 °C for 1 hour in a microwave reactor. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude residue. The obtained residue was purified by silica gel column chromatography (Biotage, elution: 50% ethyl acetate / petroleum ether) to give tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (401 mg, 0.755 mmol, 55.9%) as a brown solid.

[0320] Example 171 A solution of well-stirred tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (400 mg, 0.794 mmol) / anhydrous acetonitrile (4.0 mL) in a microwave vial (30 mL) was added with benzenesulfonic acid (126 mg, 0.794 mmol) at ambient temperature under a nitrogen atmosphere, and heated at 120 °C for 2 hours in a microwave reactor. After completion of the reaction, the excess solvent was removed under reduced pressure from this reaction mixture to obtain a crude compound. Purification was carried out using preparative HPLC to obtain 6-amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile (177.94 mg, 0.413 mmol, 52.0%) as a white solid. Preparative HPLC method details: Column: XBridge C18 (150 x 19) mm, 5 μm, Mobile phase A: 0.1% aqueous TFA solution, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: LCMS: Column: XBridge C8 (50 x 4.6 mm), 5 μm, Wavelength: 220 nm; Mobile phase; 0.1% aqueous TFA solution and acetonitrile; RT = 1.96 min; MS(ES): m / z = 430.0 (M+H) + ; Purity 99.42%; HPLC: Kinetex EVO C18 (100 x 4.6) mm, 2.6 μm; Mobile phase A: 0.05% aqueous TFA solution; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 7.14 min, Purity: 99.69%; 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.97 - 7.84 (m, 5H), 6.96 (s, 1H), 5.17 (dd, J = 4.80, 13.40 Hz, 1H), 4.58 - 4.41 (m, 2H), 2.97 - 2.89 (m, 1H), 2.52 - 2.61 (m, 1H), 2.43 - 2.42 (m, 1H), 2.08 - 2.05 (m, 1H)

[0321] Example 172 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-propylnicotinonitrile

Chem.

[0322] Product 172B. 2,6-Dichloro-4-propylnicotinonitrile In a sealed tube under a nitrogen atmosphere, at room temperature, phosphoryl chloride (10 mL) was added dropwise to a mixture of 6-hydroxy-2-oxo-4-propyl-1,2-dihydropyridine-3-carbonitrile (3 g, 16.84 mmol) and tetramethylammonium chloride (3.69 g, 33.7 mmol), and then the mixture was heated at 145 °C for 20 h. After 20 h, TLC analysis showed that the starting material had been completely consumed. The reaction mixture was then cooled to room temperature, poured into crushed ice, and stirred for 2 h. The solution was extracted with ethyl acetate (150 mL), dried over sodium sulfate, concentrated, and 2,6-dichloro-4-propylnicotinonitrile (2.6 g, 12.07 mmol, 71.7%) was obtained as a thick syrup.

[0323] Products 172C and 172D. 2-Amino-6-chloro-4-propylnicotinonitrile and 6-amino-2-chloro-4-propylnicotinonitrile To a Teflon-lined flask (50 mL) containing a well-stirred solution of 2,6-dichloro-4-propylnicotinonitrile (2.0 g, 9.30 mmol) / ethanol (25 mL), aqueous NH3 solution (15 mL) was added at ambient temperature, and then the mixture was heated at 50 °C for 16 h. After completion of the reaction, the solvent was concentrated under reduced pressure, and the product was obtained as a mixture of positional isomers. The crude material was purified by flash silica gel (230 - 400 mesh, elution: 10 - 15% EtOAc / petroleum ether) to give 2-amino-6-chloro-4-propylnicotinonitrile (171C, 170 mg, 0.864 mmol, 9.29% yield) as a white solid. The second isomer was eluted with 30% EtOAc to give 6-amino-2-chloro-4-propylnicotinonitrile as a white solid (171D, 340 mg, 1.732 mmol, 18.62% yield).

[0324] Product 172E. tert-Butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-propylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate A well-stirred solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (250 mg, 0.562 mmol) and 2-amino-6-chloro-4-propylnicotinonitrile (100 mg, 0.511 mmol) in 1,4-dioxane (5 mL) in a microwave vial (10 mL) was added with sodium hydrogen carbonate (129 mg, 1.533 mmol) / water (1 mL) at ambient temperature under a nitrogen atmosphere. The resulting reaction mixture was bubbled with nitrogen gas for 10 minutes to degas, and then tetrakis(triphenylphosphine)palladium(0) (59.1 mg, 0.051 mmol) was added. The mixture was heated by irradiating with microwaves at 120 °C for 1 hour in a MW reactor, then poured into water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a crude residue. The crude material was purified by flash silica gel column (230 - 400 mesh, 50 - 60% EtOAc / petroleum ether) to obtain tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-propylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (130 mg, 0.152 mmol, 29.8%) as an off-white solid.

[0325] Example 172 In a microwave vial, benzenesulfonic acid (24.84 mg, 0.157 mmol) was added to a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-propylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (75 mg, 0.157 mmol) in anhydrous acetonitrile (4.0 mL) under a N2 atmosphere. The reaction vial was sealed and irradiated in a microwave reactor at 130 °C for 1 hour. After completion of the reaction, the reaction mass was concentrated and the crude product was obtained as an off-white solid. It was purified using preparative HPLC to give 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-propylnicotinonitrile·TFA (55 mg, 0.106 mmol, 67.5% yield) as a white solid. Preparative HPLC method details: Column: XSelect C18 (150x19) mm, 5 μm; Mobile phase A: 0.1% aqueous TFA, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: LCMS: Column: Kinetex XB-C18 (75x3.0) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate; Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 1.826, MS (ES): m / z = 404.2 [M+H] + ; HPLC purity: Column: Kinetex EVO C18 (100X4.6) mm, 2.6 μm; Mobile phase A: 0.05% aqueous TFA; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 6.927 min; HPLC purity: 99.68%; 1HNMR: 400 MHz (DMSO): δ 11.01 (s, 1H), 8.28 - 8.21 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 6.93 (br s, 1H), 5.15 (dd, J = 5.20, 13.20 Hz, 1H), 5.15 (dd, J = 5.20, 13.20 Hz, 1H), 2.90 (m, 1H), 2.70 - 2.50 (m, 3H), 2.46 - 2.33 (m, 3H), 2.08 - 2.01 (m, 1H), 1.74 - 1.68 (m, 2H), 0.97 (t, J = 7.60 Hz, 3H); 19 FNMR: 400 MHz (DMSO): δ -74.52

[0326] Example 173 6 - Amino - 2-(2-(2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindolin - 5 - yl)-4 - propylnicotinonitrile [Chemical formula] Product 173A. tert - Butyl (S)-5 - amino - 4-(5-(6 - amino - 3 - cyano - 4 - propylpyridin - 2 - yl)-1 - oxoisoindolin - 2 - yl)-5 - oxopentanoate A well-stirred solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (250 mg, 0.562 mmol) and 6-amino-2-chloro-4-propylnicotinonitrile (172D, 100 mg, 0.511 mmol) in 1,4-dioxane (5 mL) in a microwave vial (30 mL) was added with sodium hydrogen carbonate (129 mg, 1.533 mmol) / water (1 mL) at ambient temperature under a nitrogen atmosphere. The resulting reaction mixture was bubbled with nitrogen gas for 10 minutes for degassing. Then, tetrakis(triphenylphosphine)palladium(0) (59.1 mg, 0.051 mmol) was added to this reaction mixture, and the mixture was irradiated with microwaves in a MW reactor and heated at 120 °C for 1 hour. The reaction mixture was then added to water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by flash silica gel column (230 - 400 mesh, 50 - 60% EtOAc / petroleum ether) to obtain tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-propylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (205 mg, 0.388 mmol, 76%) as an off-white solid.

[0327] Example 173 In a microwave vial, benzenesulfonic acid (66.2 mg, 0.419 mmol) was added to a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-propylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 0.419 mmol) in anhydrous acetonitrile (4.0 mL) under an N2 atmosphere. The reaction vial was sealed and irradiated with microwaves at 130 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated and the crude product was obtained as an off-white solid. Purification using preparative HPLC gave 6-amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-propylnicotinonitrile·TFA (49 mg, 0.093 mmol, 22.3%) as a white solid. Preparative HPLC method details: Column: XSelect C18 (150x19) mm, 5 μm; Mobile phase A: 0.1% aqueous TFA; Mobile phase B: acetonitrile; Flow rate: 15 mL / min Analysis data: LCMS: Column: Kinetex XB-C18 (75x3.0) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 1.340, MS (ES): m / z = 404.2 [M+H] + ; HPLC purity: Column: XBridge C8 (50x4.6) mm, 3.5 μm; Mobile phase: A: 0.1% aqueous TFA; Mobile phase B: acetonitrile; Flow rate: 2.0 mL / min; RT = 2.788 min; Purity: 99.83%; 1 1H NMR: 400 MHz (DMSO): δ 11.03 (s, 1H), 7.93 (s, 1H), 7.84 (s, 2H), 7.12 (br s, 2H), 6.44 (s, 1H), 5.16 (dd, J = 4.80, 13.40 Hz, 1H), 4.48 (dd, J = 17.20, 52.80 Hz, 2H), 2.94 (m, 1H), 2.60 - 2.66 (m, 3H), 2.50 (m, 1H), 2.05 (m, 1H), 1.66 (q, J = 7.20 Hz, 2H), 0.97 (t, J = 7.20 Hz, 3H); 19FNMR: 400 MHz (DMSO): δ -74.73

[0328] Example 174 6-Amino-4-(difluoromethyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile

Chemical formula

[0329] Example 174 To a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-(difluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 0.412 mmol) in anhydrous acetonitrile (4.0 mL) in a microwave vial, benzenesulfonic acid (65.2 mg, 0.412 mmol) was added under a N2 atmosphere. The reaction vial was sealed and irradiated with microwave at 130 °C for 1 hour. After completion of the reaction, the reaction mass was concentrated and the crude product was obtained as an off-white solid. It was purified using preparative HPLC to give 6-amino-4-(difluoromethyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (55 mg, 0.133 mmol, 32.4%) as a white solid. Preparative HPLC method details: Column: XBridge C18 (250x19) mm, 5 μm; Mobile phase A: 0.1% aqueous formic acid; Mobile phase B: acetonitrile; Flow rate: 15 mL / min Analytical data: LCMS: Column: Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 1.153, MS(ES): m / z = 412.2 [M+H] + ; HPLC purity: Column: Kinetex EVO C18 (100x4.6) mm, 2.6 μm; Mobile phase A: 0.05% aqueous TFA; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 5.230 min; Purity: 99.85%; 1HNMR: 400 MHz (DMSO): δ 11.02 (s, 1H), 7.95 (s, 1H), 7.90 - 7.83 (m, 2H), 7.64 (s, 2H), 7.15 (t, J = 53.60 Hz, 1H), 6.80 (s, 1H), 5.17 (dd, J = 5.20, 13.20 Hz, 1H), 4.49 (dd, J = 17.60, 52.00 Hz, 2H), 2.98 - 2.88 (m, 1H), 2.70 - 2.62 (m, 1H), 2.50 - 2.42 (m, 1H), 2.09 - 2.03 (m, 1H)

[0330] Example 175 2 - Amino - 6-(2-(2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindolin - 5 - yl)-5-(trifluoromethyl)nicotinonitrile

Chemical Structure

[0331] Product 175C and tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate To a stirred solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (400 mg, 0.900 mmol) / 1,4-dioxane (2 mL) at room temperature was added 2-amino-6-chloro-5-(trifluoromethyl)nicotinonitrile (180 mg, 0.810 mmol), followed by potassium carbonate (311 mg, 2.251 mmol) / water (0.5 mL). The reaction mixture was degassed with nitrogen for 15 minutes, and under a nitrogen atmosphere, PdCl2(dppf)-CH2Cl2 adduct (36.8 mg, 0.045 mmol) was added and degassed again for 5 minutes. The tube was sealed and heated at 100 °C with stirring for 2 hours. The progress of the reaction was monitored by TLC, and the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to give a crude product (850 mg), which was purified by silica gel column chromatography (Isolera, eluent: 60 - 70% EtOAc / petroleum ether) to give a mixture of tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (150 mg, 0.281 mmol, 31.2%) as a brown solid.

[0332] Example 175 In a microwave vial, benzenesulfonic acid (62.8 mg, 0.397 mmol) was added to a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (150 mg, 0.397 mmol) / acetonitrile (3 mL). The reaction vial was sealed and irradiated at 120 °C for 1 hour in a microwave reactor. The mixture was concentrated under reduced pressure to obtain a crude product (250 mg), which was purified by preparative HPLC to obtain both positional isomers. Preparative HPLC method details: Column: Sunfire C18 (150 x 19) mm, 5 μm, Mobile phase A: 0.1% aqueous TFA, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analytical data for positional isomer 1: 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-(trifluoromethyl)nicotinonitrile (7 mg, 0.016 mmol, 4.0%); pale yellow solid; HPLC: Column: Kinetex Biphenyl (100 x 4.6) mm, 2.6 μm, Mobile phase A: 0.05% aqueous TFA, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 6.891 min; Purity = 97.63% LCMS: Column: Kinetex XB-C18 (75 x 30) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 1.51 min, Purity = 99.47%; 1H-NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.41 (s, 1H), 7.82 (d, J = 8.00 Hz, 1H), 7.74 (bs, 2H), 7.65 (s, 1H), 7.54 (d, J = 8.00 Hz, 1H), 5.11 (dd, J = 4.80, 13.40 Hz, 1H), 4.53 (d, J = 17.60 Hz, 1H), 4.39 (d, J = 17.60 Hz, 1H), 2.85 - 2.93 (m, 1H), 2.61 - 2.65 (m, 1H), 2.40 - 2.43 (m, 1H), 2.06 - 2.07 (m, 1H)

[0333] Example 176 2-Amino-4-(difluoromethyl)-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile

Chemical Structure

[0334] Example 176 A solution of well-stirred tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-(difluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 0.618 mmol) in anhydrous acetonitrile (3.0 mL) in a microwave vial (30 mL) was added with benzenesulfonic acid (98 mg, 0.618 mmol) at ambient temperature under a nitrogen atmosphere and heated at 120 °C for 2 hours in a microwave reactor. After completion of the reaction, the excess solvent was removed under reduced pressure from this reaction mixture to obtain a crude compound. It was purified using preparative HPLC to obtain 2-amino-4-(difluoromethyl)-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (101.20 mg, 0.244 mmol, 39.5%) as an off-white solid. Details of preparative purification method: Column: XBridge C18 (250x19) mm, 5 μm, Mobile phase A: 0.1% aqueous TFA solution, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: LCMS: Column: Kinetex XB-C18 (75x30) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 1.49 min, Purity = 92.25% MS(ES): m / z = 412.2 (M+H) + ; HPLC: Kinetex EVO C18 (100 x 4.6) mm, 2.6 μm; Mobile phase A: 0.05% aqueous TFA solution; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 7.14 min, Purity: 99.29%; 1H-NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.33 (s, 1H), 8.26 (dd, J = 1.20, 8.00 Hz, 1H), 7.88 (d, J = 8.40 Hz, 1H), 7.55 (s, 1H), 7.43 (s, 2H), 7.17 (t, J = 54.00 Hz, 1H), 5.18 - 5.14 (m, 1H), 4.56 (d, J = 17.60 Hz, 1H), 4.43 (d, J = 17.20 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.68 - 2.64 (m, 1H), 2.40 - 2.33 (m, 1H), 2.08 - 2.05 (m, 1H)

[0335] Example 177 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile

Chemical Structure

[0336] Product 177B. tert-Butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate A solution of well-stirred 2-amino-6-chloro-4-(trifluoromethyl)nicotinonitrile (90 mg, 0.406 mmol) and tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (180 mg, 0.406 mmol) in a microwave vial (30 mL) was added with 2.0 M sodium bicarbonate (85 mg, 1.015 mmol) / water (0.2 mL) at ambient temperature under a nitrogen atmosphere. The resulting reaction mixture was bubbled with nitrogen gas for 10 minutes for degassing, and then tetrakis(triphenylphosphine)palladium(0) (14.08 mg, 0.012 mmol) was added to this mixture, and it was heated at 120 °C for 1 hour in a microwave reactor. After cooling to room temperature, this reaction mixture was poured into water (30 mL), extracted with EtOAc (2 x 50 mL), the organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude residue. The obtained residue was purified by silica gel column chromatography (Biotage, elution: 90% ethyl acetate / petroleum ether) to give tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (130 mg, 0.167 mmol, 41.1%) as a pale brown solid.

[0337] Example 177 A solution of well-stirred tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (130 mg, 0.258 mmol) in anhydrous acetonitrile (2.0 mL) in a microwave vial (30 mL) was added with benzenesulfonic acid (40.8 mg, 0.258 mmol) at ambient temperature under a nitrogen atmosphere, and heated at 120 °C for 2 hours in a microwave reactor. After the completion of the reaction was indicated by LCMS, the excess solvent was removed under reduced pressure from this reaction mixture to obtain a crude compound. The obtained crude compound was purified using preparative HPLC to obtain 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile (45 mg, 0.101 mmol, 39.0%) as an off-white solid. Preparative HPLC method details: Column: Sunfire C18 (150 x 19) mm, 5 μm, Mobile phase A: 0.1% aqueous TFA solution, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: LCMS: Column: Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm, Mobile phase A: 5 mM ammonium formate and Mobile phase B: ACN; RT = 1.96 min; MS(ES): m / z = 428.2 (M-H) + ; LCMS purity 99.91% HPLC: Kinetex EVO C18 (100 x 4.6) mm, 2.6 μm; Mobile phase A: 0.05% aqueous TFA solution; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 7.14 min, Purity: 96.11%; 1 1H-NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.33 - 8.30 (m, 2H), 7.88 (d, J = 8.00 Hz, 1H), 7.66 (d, J = 10.40 Hz, 3H), 5.18 - 5.14 (m, 1H), 4.58 - 4.42 (m, 2H), 2.97 - 2.89 (m, 1H), 2.65 - 2.53 (m, 1H), 2.48 - 2.41 (m, 1H), 2.07 - 2.02 (m, 1H)

[0338] Example 178 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile [Chemical formula] Products 178A and 178B. 2-Amino-6-chloro-4-isopropylnicotinonitrile and 6-amino-2-chloro-4-isopropylnicotinonitrile To a tinclave flask (50 mL) containing a well-stirred solution of 2,6-dichloro-4-isopropylnicotinonitrile (1.0 g, 4.65 mmol) / ethanol (10 mL), aqueous ammonium hydroxide solution (40 mL, 1027 mmol) was added at ambient temperature, and the mixture was heated at 50 °C for 16 h. After completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude product as a mixture of positional isomers. The obtained residue was purified by silica gel column chromatography (Biotage, elution: 20% ethyl acetate / petroleum ether) to give 2-amino-6-chloro-4-isopropylnicotinonitrile (178A, 0.1 g, 0.504 mmol, 10.8%) and 6-amino-2-chloro-4-isopropylnicotinonitrile (178B, 0.24 g, 1.173 mmol, 25.2%) as white solids.

[0339] Product 178C. tert-Butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate A well-stirred solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (0.2 g, 0.45 mmol), 2-amino-6-chloro-4-isopropylnicotinonitrile (0.088 g, 0.45 mmol) and 2-amino-6-chloro-4-propylnicotinonitrile (100 mg, 0.511 mmol) in 1,4-dioxane (5 mL) in a microwave vial (10 mL) was charged with sodium bicarbonate (0.095 g, 1.13 mmol) / water (1 mL) at ambient temperature under a nitrogen atmosphere and degassed by bubbling with nitrogen gas for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.052 g, 0.045 mmol) was added and the resulting reaction mixture was heated at 120 °C for 1 hour by MW. After cooling, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude residue. The obtained crude product was purified by flash silica gel column chromatography (230 - 400 mesh, Biotage, elution: 50 - 60% ethyl acetate / petroleum ether) to give tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.12 g, 0.174 mmol, 38.7%) as a pale brown liquid.

[0340] Example 178 In a microwave vial, to a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-4-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.12 g, 0.251 mmol) / anhydrous acetonitrile (4.0 mL) was added benzenesulfonic acid (0.040 g, 0.251 mmol) under a N2 atmosphere. The vial was sealed and irradiated with microwave at 130 °C for 1 hour. After completion of the reaction, the reaction mass was concentrated and the crude product was obtained as an off-white solid. The product was purified by preparative HPLC, and the fractions were lyophilized to give 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile·TFA (35 mg, 0.062 mmol, 24.87% yield). Preparative HPLC method details: Column: XBridge C-18 (150x19) mm 5μm; Mobile phase A: 0.1% aqueous TFA, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: LCMS: RT = 1.78 min; ACN / H2O (containing ammonium formate), Kinetex XB-C18 (75 x 3.0) mm, 2.6μm, (wavelength = 220 nm); MS (ES): m / z = 404.2 [M+1] + ; HPLC: Mobile phase A: 0.05% aqueous TFA; Mobile phase B: ACN; Flow rate: 1.0 mL / min; Kinetex EVO C18 (100 x 4.6) mm, 2.6μm, RT = 6.75 min, Purity: 95.55%; Kinetex Biphenyl (100 x 4.6) mm, 2.6μm, RT = 7.20 min, Purity: 92.39%; 1HNMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 7.60 Hz, 1H), 7.84 (d, J = 8.00 Hz, 1H), 7.32 (s, 1H), 6.94 (bs, 2H), 5.14 - 5.18 (m, 1H), 4.53 - 4.57 (m, 1H), 4.40 - 4.44 (m, 1H), 3.10 - 3.17 (m, 1H), 2.89 - 2.97 (m, 1H), 2.60 - 2.68 (m, 1H), 2.34 - 2.43 (m, 1H), 2.03 - 2.10 (m, 1H), 1.30 (d, J = 1.60 Hz, 6H)

[0341] Example 179 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile [Chemical formula] Product 179A. tert-Butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate Well-stirred tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (0.2 g, 0.450 mmol) and 6-amino-2-chloro-4-isopropylnicotinonitrile (0.088 g, 0.450 mmol) / 1,4-dioxane (5 mL) solution were added to a microwave vial (30 mL) under a nitrogen atmosphere. Sodium bicarbonate (0.095 g, 1.125 mmol) / degassed water (2 mL) was added at ambient temperature. The mixture was further bubbled with nitrogen gas for 10 minutes to degas, then tetrakis(triphenylphosphine)palladium(0) (0.052 g, 0.045 mmol) was added, and irradiated with MW and heated at 120 °C for 1 hour. After cooling to room temperature, the reaction mixture was added to water (30 mL), extracted with EtOAc (2 x 50 mL), the organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a crude residue. The obtained crude product was purified by flash silica gel column chromatography (230 - 400 mesh, Biotage, elution: 50 - 60% ethyl acetate / petroleum ether) to give tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.13 g, 0.220 mmol, 48.9%) as a pale brown liquid.

[0342] Example 179 In a microwave vial, to a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-4-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.13 g, 0.272 mmol) / anhydrous acetonitrile (4.0 mL) under N2 atmosphere, benzenesulfonic acid (0.043 g, 0.272 mmol) was added. The reaction vial was sealed and irradiated with MW and heated at 130 °C for 1 h. After completion of the reaction, the reaction mass was concentrated and the crude product was obtained as an off-white solid. Purification was carried out using preparative HPLC. The pure fraction was lyophilized to give 6-amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile (23 mg, 0.056 mmol, 20.43% yield) as a white solid. Preparative HPLC method details: Column: XBridge C-18 (150x19) mm; 5 μm; Mobile phase A: 0.1% aqueous formic acid, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: LCMS: Column - Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm, Wavelength = 220 nm; Mobile phase: 5 mM ammonium formate / water and acetonitrile; RT = 1.43 min; MS(ES): m / z = 404.2 [M+1] + ; HPLC: Mobile phase A: 0.05% aqueous TFA; Mobile phase B: ACN:0.05% aqueous TFA; Flow rate: 1.0 mL / min; Kinetex EVO C18 (100 x 4.6) mm, 2.6 μm, RT = 5.14 min, Purity: 95.55%; Kinetex Biphenyl (100 x 4.6) mm, 2.6 μm, RT = 5.78 min, Purity: 92.39%; 1HNMR 400MHz (DMSO) δ 11.02 (s, 1H), 7.93 (s, 1H), 7.84 (s, 2H), 7.12 (s, 2H), 6.50 (s, 1H), 5.15 - 5.17 (m, 1H), 4.52 - 4.56 (m, 1H), 4.39 - 4.43 (m, 1H), 3.07 - 3.12 (m, 1H), 2.97 - 2.98 (m, 1H), 2.64 - 2.68 (m, 1H), 2.51 - 2.60 (m, 1H), 2.04 - 2.07 (m, 1H), 1.27 (d, J = 6.40Hz, 6H)

[0343] Example 180 6 - Amino - 2 - (2 - (2,6 - dioxopiperidin - 3 - yl) - 1 - oxoisoindolin - 5 - yl) - 5 - methylnicotinonitrile [Chemical formula] Product 180A. 2 - Chloro - 5 - cyano - 3 - methylpyridine 1 - oxide To a one - necked round - bottom flask (100 mL) containing a well - stirred solution of 6 - chloro - 5 - methylnicotinonitrile (2.0 g, 13.11 mmol) / dry dichloromethane (20 mL), trifluoroacetic anhydride (1.851 mL, 13.11 mmol) and urea peroxide (1.233 g, 13.11 mmol) were added at 0 °C under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 12 h and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with 10% saturated bicarbonate solution (50 mL), the aqueous layer was extracted with dichloromethane (2 x 100 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain a crude compound. The residue obtained was purified by silica gel column chromatography (Biotage, elution: 60% EtOAc / petroleum ether) to give 2 - chloro - 5 - cyano - 3 - methylpyridine 1 - oxide (1.01 g, 5.32 mmol, 40.6%) as a yellow solid.

[0344] Product 180B. 2,6 - Dichloro - 5 - methylnicotinonitrile A solution of 2-chloro-5-cyano-3-methylpyridine 1-oxide (1.0 g, 5.93 mmol) / POCl3 (5.53 mL, 59.3 mmol) was heated at 90 °C for 3 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove excess POCl3. The resulting residue was poured into crushed ice (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated to obtain a crude residue. The obtained residue was purified by silica gel column chromatography (Biotage, elution: 20% EtOAc / petroleum ether) to obtain 2,6-dichloro-5-methylnicotinonitrile (0.890 g, 4.03 mmol, 67.9%) as a brown solid.

[0345] Product 180B. 6-Amino-2-chloro-5-methylnicotinonitrile In a 50 mL tinclave, a well-stirred solution of 2,6-dichloro-4-(trifluoromethyl)nicotinonitrile (2.0 g, 8.30 mmol) and ammonium hydroxide (1.616 mL, 41.5 mmol) / ethanol (20 mL) was heated at 50 °C for 12 hours. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude substance. This was purified by flash silica gel column chromatography (230 - 400 mesh, 10 - 30% EtOAc / petroleum ether) to obtain 6-amino-2-chloro-5-methylnicotinonitrile (135 mg, 0.746 mmol, 15.5%) and 2-amino-6-chloro-5-methylnicotinonitrile (181B, 25 mg, 0.115 mmol, 2.4%) as white solids.

[0346] Product 180C. tert-Butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate A microwave vial (30 mL) containing a well-stirred solution of 6-amino-2-chloro-5-methylnicotinonitrile (180B, 130 mg, 0.776 mmol) and tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (345 mg, 0.776 mmol) was charged with 2.0 M sodium bicarbonate (163 mg, 1.939 mmol) / water (0.3 mL) under a nitrogen atmosphere, and the mixture was bubbled with nitrogen gas and degassed for 10 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (26.9 mg, 0.023 mmol) was added to this mixture, and the mixture was heated at 120 °C for 1 hour in a microwave reactor. The progress of the reaction was monitored by TLC and LCMS, and the reaction mixture was then added to water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude residue. The obtained residue was purified by silica gel column chromatography (Biotage, elution: 90% ethyl acetate / petroleum ether) to give tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (302 mg, 0.629 mmol, 81%) as a brown solid.

[0347] Example 180 A solution of well-stirred tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 0.667 mmol) / anhydrous acetonitrile (3.0 mL) in a microwave vial (30 mL) was added with benzenesulfonic acid (106 mg, 0.667 mmol) at ambient temperature under a nitrogen atmosphere, and heated at 120 °C for 2 hours in a microwave reactor. After the completion of the reaction was indicated by LCMS, the excess solvent was removed under reduced pressure from the reaction mixture to obtain the crude compound. The crude material was purified by preparative HPLC to obtain 6-amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methylnicotinonitrile·TFA (121 mg, 0.244 mmol, 36.5%) as an off-white solid. Preparative HPLC method details: Column: XSelect C18 (150 x 19) mm, 5 μm, Mobile phase A: 0.1% aqueous TFA solution, Mobile phase B: acetonitrile, Flow rate: 15 mL / min Analysis data: LCMS: Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase A: 0.1% aqueous TFA solution; Mobile phase B: 0.1% TFA / ACN; RT = 1.38 min; MS(ES): m / z = 376.1(M+H) + ; LCMS purity 93.53%; HPLC: Kinetex Biphenyl (100 x 4.6) mm, 2.6 μm; Mobile phase A: 0.05% aqueous TFA solution; Mobile phase B: 0.05% TFA / ACN; Flow rate: 1.0 mL / min; RT: 4.88 min, Purity: 98.65%; 1H-NMR (400 MHz, DMSO-d6) δ 11.03 (bs, 1H), 7.96 (s, 1H), 7.89 - 7.84 (m, 2H), 7.74 (d, J = 0.80 Hz, 1H), 7.03 (s, 2H), 5.16 (dd, J = 5.20, 13.20 Hz, 1H), 4.55 (d, J = 17.60 Hz, 1H), 4.41 (d, J = 17.60 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.68 - 2.67 (m, 1H), 2.51 - 2.34 (m, 1H), 2.12 (s, 3H), 2.08 - 2.03 (m, 1H)

[0348] Example 181 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methoxynicotinonitrile

Chemical Structure

[0349] Product 181B. tert-Butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate A stirred solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (250 mg, 0.563 mmol) / 1,4-dioxane (2 mL) was added with 2-amino-6-chloro-5-methoxynicotinonitrile (93 mg, 0.506 mmol) at room temperature, followed by potassium carbonate (194 mg, 1.407 mmol) / water (0.5 mL). The mixture was degassed with nitrogen for 15 minutes, and PdCl2(dppf)-CH2Cl2 adduct (22.97 mg, 0.028 mmol) was added thereto under a nitrogen atmosphere. The tube was sealed, heated at 100 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (Isolera, eluent: 60-70% EtOAc / hexane) to obtain tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (80 mg, 0.079 mmol, 14.0%) as a brown solid.

[0350] Example 181 To a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-5-cyano-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (80 mg, 0.172 mmol) / anhydrous acetonitrile (3 mL) in a microwave vial was added benzenesulfonic acid (27.2 mg, 0.172 mmol). The reaction vial was sealed and irradiated at 120 °C for 1 hour in a microwave reactor. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product (150 mg). The residue obtained was purified by preparative HPLC to obtain 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methoxynicotinonitrile·TFA (14 mg, 0.027 mmol, 15.9%) as a white solid. Fractional HPLC method details: Column: Sunfire C18 (150 x 19) mm, 5 μm, Mobile phase A: 0.1% TFA aqueous solution, Mobile phase B: Acetonitrile, Flow rate: 15 mL / min Analysis data: HPLC: Column: Kinetex Biphenyl (100 x 4.6) mm, 2.6 μm, Mobile phase A: 0.05% TFA aqueous solution, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 4.98 min; Purity = 98.58%; LCMS: Column: Kinetex XB-C18 (75 x 30) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate, Mobile phase B: ACN, Flow rate: 1.0 mL / min; RT = 2.597 min, MS(ES): m / z = 392.0 [M+1] + ; Purity = 98.98%; 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 8.00 Hz, 1H), 7.85 (d, J = 7.60 Hz, 1H), 7.51 (bs, 2H), 5.16 (dd, J = 5.20, 13.40 Hz, 1H), 4.55 (d, J = 17.60 Hz, 1H), 4.42 (d, J = 17.60 Hz, 1H), 3.41 (s, 3H), 2.90 - 2.94 (m, 1H), 2.60 - 2.68 (m, 1H), 2.41 - 2.45 (m, 1H), 2.03 - 2.06 (m, 1H)

[0351] Example 182 6-Amino-5-cyclopropyl-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile

Chemical Structure

[0352] Product 182C. tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-cyclopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate A well-stirred solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (252 mg, 0.568 mmol) and 6-amino-2-chloro-5-cyclopropylnicotinonitrile (182B, 100 mg, 0.516 mmol) in 1,4-dioxane (8 mL) in a microwave vial (30 mL) was added sodium hydrogen carbonate (130 mg, 1.549 mmol) / water (2 mL) at ambient temperature, and the mixture was bubbled with nitrogen gas and degassed for 10 minutes. Then tetrakis(triphenylphosphine)palladium(0) (59.7 mg, 0.052 mmol) was added to this mixture, and the mixture was heated at 120 °C for 90 minutes by microwave irradiation in a MW reactor. The reaction mixture was diluted with EtOAc (25 mL), filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude material was purified by flash silica gel column (230 - 400 mesh, 80 - 90% EtOAc / petroleum ether) to give tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-cyclopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (195 mg, 0.373 mmol, 72.3% yield) as a pale brown solid.

[0353] Example 182 In a microwave vial, to a stirred solution of tert-butyl (S)-5-amino-4-(5-(6-amino-3-cyano-5-cyclopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (190 mg, 0.400 mmol) in anhydrous acetonitrile (7.0 mL) under a N2 atmosphere, benzenesulfonic acid (63.2 mg, 0.400 mmol) was added. The reaction vial was sealed and irradiated with microwave at 130 °C for 90 minutes. After completion of the reaction, the reaction mass was concentrated and the crude product was obtained as an off-white solid. It was purified using preparative HPLC to obtain 6-amino-5-cyclopropyl-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile·TFA (107 mg, 0.207 mmol, 51.7%) as a white solid. Analysis data: LCMS: Column: Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate aqueous solution; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 1.595, MS (ES): m / z = 402.0 [M+H] + ; HPLC: Column: Kinetex EVO C18 (100 x 4.6) mm, 2.6 μm; Mobile phase A: 0.05% TFA aqueous solution; Mobile phase B: ACN; Flow rate: 1.0 mL / min; RT = 5.598 min; Purity: 99.51%; 1 1H NMR: 400 MHz (DMSO) δ 11.02 (s, 1H), 7.95 (s, 1H), 7.90 - 7.83 (m, 2H), 7.54 (s, 1H), 7.15 (br s, 2H), 5.16 (dd, J = 4.80, 13.40 Hz, 1H), 4.55 (d, J = 17.60 Hz, 1H), 4.41 (d, J = 17.60 Hz, 1H), 2.90 (m, 1H), 2.63 (m, 1H), 2.45 (m, 1H), 2.05 (m, 1H), 1.70 (m, 1H), 0.92 (m, 2H), 0.67 (m, 2H); 19 19F NMR: 400 MHz (DMSO): δ -74.49

[0354] Example 183 2-Amino-5-cyclopropyl-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile

Chemical formula

Claims

1. Formula (I) 【Chemical Formula 1】 [wherein ring A is 【Chemical 2】 ; Each R 1 are independently F, Cl, Br, -CN, -OH, -NO 2 , 0 to 6 R 1a C replaced with 1-6 Alkyl, 0 to 6 R 1a C replaced with 1-3 Alkoxy, -CR x R x OCR x R x (phenyl), -NR y R y , -NR x C(O)H, -NR x C(O)(C 1-2 alkyl), -NR x C(O)NR x R x , -C(O)H, -C(O)OH, -C(O)O(C 1-3 alkyl), -C(O)NR x R x , -C(O)NR x (C 3-6 Cycloalkyl), -OC(O)(C 1-3 Alkyl), -SO 2 (C 1-3 alkyl), -NHN(C 1-2 Alkyl) 2 , -CH 2 CH 2 Si(CH 3 ) 3 or C 3-6 a cyclic group selected from cycloalkyl, phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, and dioxidothiomorpholinyl, said cyclic group being selected from 0 to 4 R 1b Replaced with; Each R 1a is independently F, Cl, -CN, -OH, C 1-2 alkoxy, C 1-2 fluoroalkoxy, -SO 2 (C 1-3 alkyl), or phenyl; Each R 1b is independently F, Cl, C 1-2 alkyl, C 1-2 fluoroalkyl, C 1-2 alkoxy, C 1-2 fluoroalkoxy, -C(O)(C 1-3 alkyl), -SO 2 (C 1-3 alkyl), or -CH 2 (phenyl); Each R x is independently H or -CH 3 ; Each R y is independently H or C 1-6 alkyl; and n is 0, 1, 2, 3, or 4] and salts thereof.

2. wherein Each R 1 are independently F, Cl, Br, -CN, -OH, -NO 2 , 0 to 6 R 1a C replaced with 1-5 Alkyl, 0 to 5 R 1a C replaced with 1-2 Alkoxy, -CR x R x OCH 2 (phenyl), -NR y R y , -NR x C(O)CH 3 , -NR x C(O)NR x R x , -C(O)H, -C(O)OH, -C(O)O(C 1-2 alkyl), -C(O)NR x R x , -C(O)NR x (cyclopropyl), -OC(O)(C 1-2 Alkyl), -SO 2 (C 1-2 alkyl), -NHN(CH 3 ) 2 , -CH 2 CH 2 Si(CH 3 ) 3 or C 3-6 a cyclic group selected from cycloalkyl, phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, and dioxidothiomorpholinyl, said cyclic group being selected from 0 to 3 R 1b Replaced with; Each R 1b is independently F, Cl, C 1-2 alkyl, -CH 2 F, -CHF 2 , -CF 3 , C 1-2 alkoxy, -OCF 3 , -C(O)(C 1-2 alkyl), or -SO 2 (C 1-2 alkyl); and n is 0, 1, 2, or 3, the compound according to Claim 1 or a salt thereof.

3. wherein Each R 1 is independently F, Cl, Br, -CN, -OH, -NO 2 , -CH 3 , -CH 2 CH 3 , -CHCH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CF 3 , -CH 2 Cl, -CH 2 CN, -CH 2 (phenyl), -CH 2 OH, -CH 2 OCH 2 (phenyl), -OCH 3 , -OCH 2 CH 3 , -OCH 2 (phenyl), -NH 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -NH(CH(CH 3 )CH 2 CH 3 ), -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NHC(O)CH 3 , -N(CH 3 )C(O)CH 3 , -C(O)H, -C(O)OCH 3 , -C(O)NH(cyclopropyl), -C(O)NH 2 , -C(O)N(CH 3 ) 2 , -CH 2 CH 2 Si(CH 3 ) 3 , -OC(O)CH 3 , -NHN(CH 3 ) 2 is cyclopropyl, phenyl, pyridinyl, (benzyl)morpholinyl, (methylsulfonyl)piperazinyl, or acetylpiperazinyl; and n is 0, 1, 2, or 3, the compound according to Claim 1 or a salt thereof.

4. wherein ring A is [Chemical 3] ; the compound according to Claim 1 or a salt thereof.

5. 【Chemical Formula 4】 wherein ring A is ; the compound according to any one of Claims 1 to 3 or a salt thereof. 【Chemical Formula 5】

6. wherein ring A is ; the compound according to any one of Claims 1 to 3 or a salt thereof. 【Chemical Formula 6】

7. Each R 1 is independently F, Cl, Br, -CN, -OH, -NO 2 , -CH 3 , -OCH 3 , -NH 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -NHC(O)CH 3 , -NHN(CH 3 ), 2 cyclopropyl, phenyl, (benzyl)morpholinyl, (methylsulfonyl)piperazinyl, or acetylpiperazinyl; and wherein ring A is ; n is 0, 1, 2, or 3, the compound according to any one of Claims 1 to 3 or a salt thereof. 【Chemical Formula 7】

8. Each R 1 is independently F, Cl, -CN, -OH, -CH 3 , -OCH 3 , -OCH 2 (phenyl), -NH 2 , -N(CH 3 ) 2 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CF 3 , -CH 2 Cl, -CH 2 CN, -CH 2 (phenyl), -CH 2 OH, -CH 2 OCH 2 (phenyl), -OCH 2 CH 3 , -NH(CH 3 ), -NH(CH 2 CH 3 ), or -NHC(O)CH 3 ; and wherein A is ; n is 0, 1, or 2, the compound according to any one of Claims 1 to 3 or a salt thereof. 【Chemical Formula 8】

9. Each R 1 is independently F, Cl, -OH, -CH 3 , -OCH 3 , -NH 2 , -C(O)OCH 3 , -C(O)NH(cyclopropyl), or phenyl; and wherein ring A is ; n is 0, 1, or 2, the compound according to any one of Claims 1 to 3 or a salt thereof. 【Chemical Formula 9】

10. Each R 1 is independently -CN, -NH 2 , -C(O)NH 2 , phenyl, or pyridinyl; and wherein ring A is ; n is 0, 1, or 2, the compound according to any one of Claims 1 to 3 or a salt thereof.

11. 3-(5-{8-oxa-3,5-diazatricyclo[7.4.0.0 2 ,7]trideca-1(9),2,4,6,10,12-hexen-6-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (3); the compound is 3-[1-oxo-5-(quinolin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (1); 3-[5-(4-aminoisoxquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (2); 3-[5-(1-aminoisoxquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (4); 3-[5-(3-aminoquinoxalin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (5); 3-(1-oxo-5-{7H-pyrrolo[2,3-c]pyridazin-3-yl}-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (6); 3-[1-oxo-5-(quinoxalin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (7); 3-[5-(4-Aminoquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (8); 3-[1-Oxo-5-(quinazolin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (9); 3-(5-{2-[(Butan-2-yl)amino]-[1,3]thiazolo[5,4-b]pyridin-5-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (10); 3-(5-{7-Fluoro-1H-pyrrolo[3,2-c]pyridin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (11); 3-[5-(4-Methoxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (12); 3-[1-Oxo-5-(4-phenylquinolin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (13); N-Cyclopropyl-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinoline-4-carboxamide (14); 3-{5-[6-Chloro-4-(diethylamino)quinazolin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (15); 3-[5-(4-Amino-6,7-dimethoxyquinazolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (16); 3-[5-(6-Methoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (17); 3-[5-(6-Chloroquinoxalin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (18); 3-[5-(7-Fluoroisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (19); 3-[5-(5-Fluoroisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (20); 3-[5-(1,5-Naphthyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (21); 3-[5-(4-Aminoquinazolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (22); 3-[5-(6-Methylisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (23); 3-[5-(4-Methylquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (24); 3-[5-(3-Aminoisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (25); 3-[5-(6-Fluoroquinoxalin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (26); 3-[5-(6-Chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (27); 3-[5-(7-Chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (28); 3-[5-(6-Methoxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (29); Ethyl 3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinoxaline-2-carboxylate (30); Methyl 2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinoline-6-carboxylate (31); 3-[5-(3-Methylquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (32); 3-[5-(8-Methoxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (33); 3-[5-(8-Chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (34); 3-[5-(6-Fluoroquinazolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (35); 3-[5-(3-Chloroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (36); 3-[5-(4-Hydroxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (37); 3-[5-(6-Fluoroquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (38); 3-[5-(6-Methylquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (39); 3-[5-(6-Hydroxyquinolin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (40); Methyl 2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]quinazoline-7-carboxylate (41); 3-(5-{5-Amino-3-[2-(trimethylsilyl)ethyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (42); 3-[5-(2-Amino-9H-purin-6-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (43); 3-[5-(6-Amino-7H-purin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (44); 3-(5-{6-Amino-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (45); 3-{5-[5-Amino-1-(2,2-dimethylpropyl)-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (46); 3-[5-(5-Amino-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (47); N-{3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}acetamide (48); 3-{5-[1-(Dimethylamino)isoquinolin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (49); 3-{5-[1-(Methylamino)isoquinolin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (50); 3-{5-[5-(Methylamino)-1,6-naphthyridin-7-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (51); N-{3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-1-yl}-N-methylacetamide (52); 3-[5-(6-Amino-1,7-naphthyridin-8-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (53); 3-[5-(3-Amino-5-methoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (54); 3-(5-(4-(4-Acetylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55); 3-(5-{4-Bromo-1H-pyrrolo[2,3-c]pyridin-7-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (56); 3-[5-(5-Amino-1,6-naphthyridin-7-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (57); 3-[5-(3,6-Dimethoxyisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (58); 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinoline-3-carbonitrile (59); 4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]thieno[3,2-c]pyridine-2-carbaldehyde (60); 3-{5-[1-Methyl-4-(methylamino)-1H-imidazo[4,5-c]pyridin-6-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (61); 3-(5-{2-Methyl-4-oxo-4H-pyrano[2,3-b]pyridin-7-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (62); 3-{5-[5,7-Dichloro-3-(dimethylamino)isoquinolin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (63); 3-[5-(1,7-Naphthyridin-8-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (64); 3-(5-{2-Aminoimidazo[1,2-b]pyridazin-6-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (65); 3-[5-(Isoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (66); 3-[5-(Isoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (67); 3-(5-(2-Amino-6-methoxypyrimidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (68); 3-(5-(6-Aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (69); 3-(5-(2-Aminopyrimidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70); 3-(1-Oxo-5-(4-phenylpyrimidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (71); 3-(1-Oxo-5-(4-(pyridin-3-yl)pyrimidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (72); 3-(5-(4-Amino-6-phenyl-1,3,5-triazin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (73); 3-(1-Oxo-5-(4-phenylpyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (74); 3-(1-Oxo-5-(4-(pyridin-2-yl)pyrimidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (75); 3-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridazine-4-carbonitrile (76); 6-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridazine-3-carbonitrile (77); 6-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridazine-3-carboxamide (78); 3-[5-(6-Amino-3-nitropyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (79); 4-Amino-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyrimidine-5-carbonitrile (80); 4-Amino-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyrimidine-5-carboxamide (81); (3S)-3-[5-(1-Aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (82); (3R)-3-[5-(1-Aminoisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (83); (3S)-3-[5-(1-Amino-4-ethoxyisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (84); 3-(5-(4-Ethoxyisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (85); 3-(5-(1-Chloro-4-ethoxyisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86); 3-(5-(2,3-Dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87); 3-(5-(1-Methylisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (88); 3-(5-(1-Cyclopropylisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (89); 1-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isoquinoline-4-carbonitrile (90); 3-(1-Oxo-5-(quinazolin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (91); 3-(5-(6-Methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (92); 3-(5-(3-Chloroquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (93); 3-(5-(3-Methoxyquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (94); 3-(5-(3-(Ethylamino)quinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95); 3-(5-(3-Hydroxyquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (96); 3-(5-(3-Cyclopropylquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (97); 3-(5-(3-Isopropylquinoxalin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (98); 3-(1-Oxo-5-(3-phenylquinoxalin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (99); 3-(5-(1,6-Naphthyridin-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100); 3-(5-(6-Amino-3-bromopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (101); 3-(5-(6-Aminoisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (102); 3-(5-(4-Methoxyisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (103); 3-(5-(3-Methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (104); 3-(5-(4-(Benzyloxy)isoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (105); 3-(5-(6-Amino-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (106); 3-(5-(3-(Hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (107); 3-(5-(4-(Hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (108); 3-(1-Oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (109); 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isonicotinonitrile (110); 2-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)acetonitrile (111); 3-(5-(6-Amino-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (112); 3-(5-(2,3-Dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (113); 3-(1-Oxo-5-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-2-yl)piperidine-2,6-dione (114); 3-(1-Oxo-5-(5,6,7,8-tetrahydroisoquinolin-3-yl)isoindolin-2-yl)piperidine-2,6-dione (115); 3-(5-(6-Amino-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (116); 3-(5-(5,6-Diaminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (117); 3-(1-Oxo-5-(1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)isoindolin-2-yl)piperidine-2,6-dione (118); 3-(5-(5-Amino-4,6-dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (119); 3-(5-(6-Amino-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120); 3-(5-(4,5-Dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (121); (3S)-3-[5-(1,8-Naphthyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (122); (S)-3-(5-(3-Aminoisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (123); (S)-N-(1-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isoquinolin-3-yl)acetamide (124); 3-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}isoquinoline-1-carbonitrile (125); 3-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}isoquinoline-1-carboxamide (126); (4S)-7-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-2H,3H,4H-pyrano[2,3-b]pyridin-4-yl acetate (127); (4R)-7-{2-[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-2H,3H,4H-pyrano[2,3-b]pyridin-4-yl acetate (128); 3-{5-[7-Chloro-4-(dimethylamino)isoquinolin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (129); 1-Amino-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N,N-dimethylisoquinoline-4-carboxamide (130); 3-[5-(1-Amino-4-methylisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (131); 3-[5-(6-Amino-3-cyclopropylpyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (132); 3-[5-(6-Aminoisoquinolin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (133); N-{1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]isoquinolin-6-yl}acetamide (134); 3-{5-[6-Amino-4-(chloromethyl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (135); 3-(1-Oxo-5-{5H,6H,7H,8H,9H-pyrido[2,3-b]azepin-2-yl}-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (136); 3-[1-Oxo-5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (137); 3-{5-[6-(2,2-Dimethylhydrazin-1-yl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (138); 3-(5-(1H-Imidazo[4,5-b]pyridin-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (139); 3-(5-(6-Amino-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140); 3-(5-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (141); 3-(5-(6-Aminopyrazin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (142); 3-(5-(2-Amino-6-methylpyrimidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (143); 3-(5-(4,6-Dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (144); 3-(5-(5-Chloro-3-hydroxyisoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (145); 3-(5-(6-Methoxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (146); 3-(5-(6-Hydroxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (148); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)isonicotinonitrile (149); 3-(5-(1-Amino-5,6,7,8-tetrahydroisoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150); 3-(5-(6-Amino-4,5-dimethylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (151); 6-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (152); 3-(5-(6-Amino-5-methoxy-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (153); 3-(5-(4-((Benzyloxy)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (154); 3-[5-(6-Methoxypyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (155); 3-[5-(1-Methoxyisoquinolin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (156); 3-[1-Oxo-5-(1-oxo-1,2-dihydroisoquinolin-3-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (157); 3-(5-{1-Benzyl-1H-pyrrolo[3,2-c]pyridin-6-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (158); 3-(1-Oxo-5-(1H-pyrrolo[3,2-c]pyridin-6-yl)isoindolin-2-yl)piperidine-2,6-dione (159); 3-(1-Oxo-5-(1H-pyrrolo[3,2-c]pyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (160); 3-(5-(1-Benzyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (161); 6-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolino-nitrile (162); 3-(5-(6-Amino-4-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (163); 3-(5-(6-Amino-4-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (164); 3-(5-(6-Amino-4-chloropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (165); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (166); N-(6-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,4-dimethylpyridin-2-yl)acetamide (167); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridine-3,5-dicarbonitrile (168); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoronicotinonitrile (169); 3-(5-(6-Amino-4-phenylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (170); 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile (171); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-propylnicotinonitrile (172); 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-propylnicotinonitrile (173); 6-Amino-4-(difluoromethyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (174); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-(trifluoromethyl)nicotinonitrile (175); 2-Amino-4-(difluoromethyl)-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (176); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)nicotinonitrile (177); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile (178); 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-isopropylnicotinonitrile (179); 6-Amino-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methylnicotinonitrile (180); 2-Amino-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methoxynicotinonitrile (181); 6-Amino-5-cyclopropyl-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (182); 2-Amino-5-cyclopropyl-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)nicotinonitrile (183); 3-(5-(6-Amino-4-(4-benzylpiperazin-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (184); 3-(5-(6-Amino-4-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (185); 3-(5-(4-(4-Acetylpiperazin-1-yl)-6-aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (186); 3-(5-(4-Methyl-6-(methylamino)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (187); 3-(5-(6-(Ethylamino)-4-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (188); or 3-(5-(4,5-Dimethyl-6-(methylamino)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (189) The compound or a salt thereof according to claim 1, which is as defined above.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition for the treatment of cancer, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 13, wherein the cancer is selected from colon cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia and melanoma.

15. A method for reducing the level, activity level or expression level of Helios protein in vitro or ex vivo cells, characterized by contacting the Helios protein with the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

16. The method according to claim 15, wherein the Helios protein is encoded by the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, or 5.

17. A pharmaceutical composition for reducing the level, activity level or expression level of Helios protein, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

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